Class of arylamide compounds useful as inhibitors of c-fms kinase

ABSTRACT

The invention relates to arylamide and hetereoarylamide compounds of Formula I: 
                         
wherein A, X, R 2  and W are set forth in the specification, as well as tautomers and pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase. Methods of treating autoimmune diseases; and diseases with an inflammatory component; treating metastasis from ovarian cancer, uterine cancer, breast cancer, colon cancer, stomach cancer, hairy cell leukemia and non-small lung carcinoma; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as osteoporosis, Paget&#39;s disease, and other diseases in which bone resorption mediates morbidity including arthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone with the compounds of Formula I, are also provided.

This application claims priority to provisional application, which isU.S. Ser. No. 60/621,192, filed Oct. 22, 2004. The complete disclosuresof the aforementioned related U.S. patent applications are herebyincorporated herein by reference for all purposes.

CROSS-REFERENCE TO RELATED APPLICATIONS

Not applicable.

BACKGROUND OP THE INVENTION

1. Field of the Invention

The invention relates to novel compounds that function as proteintyrosine kinase inhibitors. More particularly, the invention relates tonovel arylamide and hetereoarylamide compounds that function asinhibitors of c-fms kinase.

2. Description of Related Art

Protein kinases are enzymes that serve as key components of signaltransduction pathways by catalyzing the transfer of the terminalphosphate from adenosine 5′-triphosphate (ATP) to the hydroxy group oftyrosine, serine and threonine residues of proteins. As a consequence,protein kinase inhibitors and substrates are valuable tools forassessing the physiological consequences of protein kinase activation.The overexpression or inappropriate expression of normal or mutantprotein kinases in mammals has been demonstrated to play significantroles in the development of many diseases, including cancer anddiabetes.

Protein kinases can be divided into two classes: those whichpreferentially phosphorylate tyrosine residues (protein tyrosinekinases) and those which preferentially phosphorylate serine and/orthreonine residues (protein serine/threonine kinases). Protein tyrosinekinases perform diverse functions ranging from stimulation of cellgrowth and differentiation to arrest of cell proliferation. They can beclassified as either receptor protein tyrosine kinases or intracellularprotein tyrosine kinases. The receptor protein tyrosine kinases, whichpossess an extracellular ligand binding domain and an intracellularcatalytic domain with intrinsic tyrosine kinase activity, aredistributed among 20 subfamilies.

Receptor tyrosine kinases of the epidermal growth factor (“EGF”) family,which includes HER-1, HER-2/neu and HER-3 receptors, contain anextracellular binding domain, a transmembrane domain and anintracellular cytoplasmic catalytic domain. Receptor binding leads tothe initiation of multiple intracellular tyrosine kinase dependentphosphorylation processes, which ultimately results in oncogenetranscription. Breast, colorectal and prostate cancers have been linkedto this family of receptors.

Insulin receptor (“IR”) and insulin-like growth factor I receptor(“IGF-1R”) are structurally and functionally related but exert distinctbiological effects. IGF-1R over-expression has been associated withbreast cancer.

Platelet derived growth factor (“PDGF”) receptors mediate cellularresponses that include proliferation, migration and survival and includePDGFR, the stem cell factor receptor (c-kit) and c-fms. These receptorshave been linked to diseases such as atherosclerosis, fibrosis andproliferative vitreoretinopathy. These are type III Receptor tyrosinekinase family may or may not be PDGF.

Fibroblast growth factor (“FGR”) receptors consist of four receptorswhich are responsible for the production of blood vessels, for limboutgrowth, and for the growth and differentiation of numerous celltypes.

Vascular endothelial growth factor (“VEGF”), a potent mitogen ofendothelial cells, is produced in elevated amounts by many tumors,including ovarian carcinomas. The known receptors for VEGF aredesignated as VEGFR-1 (Flt-1), VEGFR-2 (KDR), VEGFR-3 (Flt-4). A relatedgroup of receptors, tie-1 and tie-2 kinases, have been identified invascular, endothelium and hematopoietic cells. VEGF receptors have beenlinked to vasculogenesis and angiogenesis.

Intracellular protein tyrosine kinases are also known as non-receptorprotein tyrosine kinases. Over 24 such kinases have been identified andhave been classified into 11 subfamilies. The serine/threonine proteinkinases, like the cellular protein tyrosine kinases, are predominantlyintracellular.

Diabetes, angiogenesis, psoriasis, restenosis, ocular diseases,schizophrenia, rheumatoid arthritis, cardiovascular disease and cancerare exemplary of pathogenic conditions that have been linked withabnormal protein tyrosine kinase activity. Thus, a need exists forselective and potent small-molecule protein tyrosine kinase inhibitors.U.S. Pat. Nos. 6,383,790; 6,346,625; 6,235,746; 6,100,254 and PCTInternational Applications WO 01/47897, WO 00/27820 and WO 02/068406 areindicative of recent attempts to synthesize such inhibitors.

SUMMARY OF THE INVENTION

The invention addresses the current need for selective and potentprotein tyrosine kinase inhibitors by providing potent inhibitors ofc-fms kinase. The invention is directed to the novel compounds ofFormula I:

or a solvate, hydrate, tautomer or pharmaceutically acceptable saltthereof, wherein:

-   A is    -   phenyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, which        may be substituted with one of chloro, fluoro, methyl, —N₃,        —NH₂, —NH(alkyl), —N(alkyl)₂, —S(alkyl), —O(alkyl),        alkylOC(O)alkyl, or 4-aminophenyl;-   W is    -   pyrrolyl (including 1H-pyrrol-2-yl), imidazolyl, (including        1H-imidazol-2-yl), isoxazolyl, oxazolyl, 1,2,4 triazolyl, or        furanyl (including furan-2-yl), any of which may be connected        through any carbon atom, wherein the pyrrolyl, imidazolyl,        isoxazolyl, oxazolyl, 1,2,4 triazolyl, or furanyl may contain        one —CN, —NO₂, —OMe, C(═NH)NOH, or —CF₃ substitution, connected        to any other carbon;-   R² is piperidinyl, pyrrolyl or pyrrolidinyl, any of which may be    independently substituted with one or two of each of the following:    chloro, fluoro, oxo, and C₍₁₋₃₎alkyl, with the proviso that R² is    connected to the ring A through the nitrogen atom;-   X is

-   Z is    -   CH or N;-   D¹ and D² are    -   hydrogens or taken together form a double bond to an oxygen;-   D³ and D⁴ are    -   hydrogens or taken together form a double bond to an oxygen;-   D⁵ is    -   hydrogen or —CH₃, wherein said —CH₃ may be relatively oriented        syn or anti;-   R_(a) and R_(b) are independently    -   hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl;-   E is    -   N, S, O, SO or SO₂, with the proviso that E may not be N if the        following three conditions are simultaneously met: Q_(a) is        absent, Q_(b) is absent, and R³ is an amino group or cyclic        amino radical wherein the point of attachment to E is N;-   Q_(a) is    -   absent, —CH₂—, —CH₂CH₂—, or C(O);-   Q_(b) is    -   absent, —NH—, —CH₂—, —CH₂CH₂—, or C(O), with the proviso that        Q_(b) may not be C(O) if Q_(a) is C(O), and further provided        that Q_(b) may not be —NH— if E is N and Q_(a) is absent,        further provided that Q_(b) may not be —NH— if R³ is an amino        group or cyclic amino radical wherein the point of attachment to        Q_(b) is N;-   R³ is    -   hydrogen, phenyl, hydroxyalkylamino (including 2-hydroxy        ethylamino), (hydroxyalkyl)₂amino, hydroxyalkyl(alkyl)amino        (including 1-hydroxyeth-2-yl(methyl)amino), alkylamino        (including methylamino), aminoalkyl (including 2-amino        isopropyl), dihydroxyalkyl (including 1,3-dihydroxy isopropyl,        1,2-dihydroxy ethyl), alkoxy (including methoxy), dialkylamino        (including dimethylamino), hydroxyalkyl (including 1-hydroxy        eth-2-yl), —COOH, —CONH₂, —CN, —SO₂-alkyl-R⁴ (including        —SO₂CH₃), —NH₂, or a 5 or six membered ring which contains at        least one heteroatom N and may optionally contain an additional        heteromoiety selected from S, SO₂, N, and O, and the 5 or 6        membered ring may be saturated, partially unsaturated or        aromatic (including piperidinyl, morpholinyl, imidazolyl, and        pyridyl) wherein aromatic nitrogen in the 5 or 6 membered ring        may be present as N-oxide (including pyridyl N-oxide), and the 5        or 6 membered ring may be optionally substituted with methyl,        halogen, alkylamino, or alkoxy (including 1 methyl imidazolyl);        R³ may also be absent, with the proviso that R³ is not absent        when E is nitrogen;-   R⁴ is    -   hydrogen, —OH, alkoxy, carboxy, carboxamido, or carbamoyl.

The compounds of Formula I are especially potent inhibitors of the c-fmsprotein tyrosine kinase.

The invention also relates to methods of inhibiting protein tyrosinekinase activity in a mammal by administration of a therapeuticallyeffective amount of at least one compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to the novel compounds of Formula I:

or a solvate, hydrate, tautomer or pharmaceutically acceptable saltthereof, wherein:

-   A is    -   phenyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, which        may be substituted with one of chloro, fluoro, methyl, —N₃,        —NH₂, —NH(alkyl), —N(alkyl)₂, —S(alkyl), —O(alkyl),        alkylOC(O)alkyl, or 4-aminophenyl;-   W is    -   pyrrolyl (including 1H-pyrrol-2-yl), imidazolyl, (including        1H-imidazol-2-yl), isoxazolyl, oxazolyl, 1,2,4 triazolyl, or        furanyl (including furan-2-yl), any of which may be connected        through any carbon atom, wherein the pyrrolyl, imidazolyl,        isoxazolyl, oxazolyl, 1,2,4 triazolyl, or furanyl may contain        one —CN, —NO₂, —OMe, C(═NH)NOH, or —CF₃ substitution, connected        to any other carbon;-   R² is piperidinyl, pyrrolyl or pyrrolidinyl, any of which may be    independently substituted with one or two of each of the following:    chloro, fluoro, oxo, and C₍₁₋₃₎alkyl, with the proviso that R² is    connected to the ring A through the nitrogen atom;-   X is

-   Z is    -   CH or N;-   D¹ and D² are    -   hydrogens or taken together form a double bond to an oxygen;-   D³ and D⁴ are    -   hydrogens or taken together form a double bond to an oxygen;-   D⁵ is    -   hydrogen or —CH₃, wherein said —CH₃ may be relatively oriented        syn or anti;-   R_(a) and R_(b) are independently    -   hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl;-   E is    -   N, S, O, SO or SO₂, with the proviso that E may not be N if the        following three conditions are simultaneously met: Q_(a) is        absent, Q_(b) is absent, and R³ is an amino group or cyclic        amino radical wherein the point of attachment to E is N;-   Q_(a) is    -   absent, —CH₂—, —CH₂CH₂—, or C(O);-   Q_(b) is    -   absent, —NH—, —CH₂—, —CH₂CH₂—, or C(O), with the proviso that        Q_(b) may not be C(O) if Q_(a) is C(O), and further provided        that Q_(b) may not be —NH— if E is N and Q_(a) is absent,        further provided that Q_(b) may not be —NH— if R³ is an amino        group or cyclic amino radical wherein the point of attachment to        Q_(b) is N;-   R³ is    -   hydrogen, phenyl, hydroxyalkylamino (including 2-hydroxy        ethylamino), (hydroxyalkyl)₂amino, hydroxyalkyl(alkyl)amino        (including 1-hydroxyeth-2-yl(methyl)amino), alkylamino        (including methylamino), aminoalkyl (including 2-amino        isopropyl), dihydroxyalkyl (including 1,3-dihydroxy isopropyl,        1,2-dihydroxy ethyl), alkoxy (including methoxy), dialkylamino        (including dimethylamino), hydroxyalkyl (including 1-hydroxy        eth-2-yl), —COOH, —CONH₂, —CN, —SO₂-alkyl-R⁴ (including        —SO₂CH₃), —NH₂, or a 5 or six membered ring which contains at        least one heteroatom N and may optionally contain an additional        heteromoiety selected from S, SO₂, N, and O, and the 5 or 6        membered ring may be saturated, partially unsaturated or        aromatic (including piperidinyl, morpholinyl, imidazolyl, and        pyridyl) wherein aromatic nitrogen in the 5 or 6 membered ring        may be present as N-oxide (including pyridyl N-oxide), and the 5        or 6 membered ring may be optionally substituted with methyl,        halogen, alkylamino, or alkoxy (including 1 methyl imidazolyl);        R³ may also be absent, with the proviso that R³ is not absent        when E is nitrogen;-   R⁴ is    -   hydrogen, —OH, alkoxy, carboxy, carboxamido, or carbamoyl.

Preferred compounds of Formula I are those wherein:

-   A is    -   phenyl which may be substituted with one of chloro, fluoro,        methyl, or 4-aminophenyl;-   X is    -   attached to the phenyl A ring para to the nitrogen substituent,        as depicted in formula II;

-   D³ and D⁴ are hydrogen.-   E is N or SO₂;-   R³ is    -   hydrogen, piperidinyl, alkylamino, hydroxyalkylamino,        (hydroxyalkyl)₂amino, alkylamino, imidazolyl, 1-methyl        imidazolylimidazolyl, pyridyl, pyridyl N-oxide, hydroxyalkyl,        —COOH, —CONH₂, —CN, —SO₂CH₃, —NH₂, morpholine; R³ may also be        absent; with the proviso that R³ is not absent when E is        nitrogen.

Preferred compounds of Formula I are those wherein

-   W is substituted with one —CN.

Other preferred compounds of Formula I are those wherein:

-   A is    -   pyridyl, which may be substituted with one of chloro, fluoro,        methyl, —N₃, —NH₂, —NH(alkyl), —N(alkyl)₂, —S(alkyl), —O(alkyl),        or 4-aminophenyl;-   W is    -   imidazolyl, (including 1H-imidazol-2-yl), which may contain one        —CN; and-   R² is    -   cycloalkyl.

More preferred compounds of Formula I are those wherein:

-   A is    -   phenyl which may be substituted with 4-aminophenyl;-   W is    -   furan-2-yl, 1H-pyrrol-2-yl, or 1H-imidazol-2-yl, either of which        may be substituted at the 4 or 5 carbons with —CN;-   R² is    -   piperidinyl which may be substituted with one of each of the        following chloro, fluoro, and C₍₁₋₃₎alkyl.

Even more preferred compounds of Formula I are those wherein:

-   W is    -   3H-2-imidazolyl-4-carbonitrile or 5-cyano-1H-pyrrol-2-yl;-   R² is    -   piperidinyl optionally substituted with fluoro or methyl;-   E is N and-   Z is CH.

Especially preferred compounds of Formula I are those wherein:

-   W is    -   imidazolyl, (including 1H-imidazol-2-yl), 1,2,4 triazolyl, or        furanyl (including furan-2-yl), any of which may be connected        through any carbon atom, wherein the imidazolyl, 1,2,4        triazolyl, or furanyl may contain one —Cl or —CN, connected to        any other carbon;-   R² is    -   cycloalkyl (including C₍₁₋₃₎alkyl substituted cycloalkyl,        further including C₍₁₋₃₎alkyl substituted cyclopentenyl, and        C₍₁₋₃₎alkyl substituted cyclohexenyl, further including 4-methyl        cyclohexenyl), C₍₁₋₃₎dialkyl substituted cycloalkyl (including        4,4-dimethyl cyclohexenyl), thiophenyl (including C₍₁₋₃₎alkyl        substituted thiophenyl, further including 2-methyl thiophenyl        and 3-methyl thiophenyl), C₍₁₋₃₎alkyl substituted phenyl        (including methyl phenyl), dihydropyranyl, and        1,1-dioxo-tetrahydrothiopyranyl;-   X is

-   E is    -   N or SO₂, with the proviso that E may not be N if the following        three conditions are simultaneously met: Q_(a) is absent, Q_(b)        is absent, and R³ is an amino group or cyclic amino radical        wherein the point of attachment to E is N; and-   R³ is    -   hydrogen, phenyl, hydroxyalkylamino (including 2-hydroxy        ethylamino), hydroxyalkyl(alkyl)amino (including        1-hydroxyeth-2-yl(methyl)amino), alkylamino (including        methylamino), aminoalkyl (including 2-amino isopropyl),        dihydroxyalkyl (including 1,3-dihydroxy isopropyl, 1,2-dihydroxy        ethyl), alkoxy (including methoxy), dialkylamino (including        dimethylamino), hydroxyalkyl (including 1-hydroxy eth-2-yl),        —COOH, —CONH₂, —CN, —SO₂CH₃, —NH₂, or a 5 or six membered ring        selected from the group consisting of: piperidinyl, morpholinyl,        imidazolyl, and pyridyl, wherein the 5 or 6 membered ring may be        optionally substituted with methyl, halogen, alkylamino, or        alkoxy (including 1 methyl imidazolyl), R³ may also be absent,        with the proviso that R³ is not absent when E is nitrogen.

Most preferred compounds of Formula I are those wherein:

-   W is    -   3H-2-imidazolyl-4-carbonitrile;-   Q_(a) is CO;    -   R³ is        -   hydrogen, piperidine, alkylamine, hydroxyalkylamine,            (hydroxyalkyl)₂amine, alkylamine, dialkylamine, imidazole,            1-methyl imidadole, pyridine, pyridine N-oxide,            hydroxyalkyl, —COOH, —CONH₂, —CN, —SO₂CH₃, —NH₂, morpholine.

The compounds of Formula I are especially potent inhibitors of the c-fmsprotein tyrosine kinase.

The invention also relates to methods of inhibiting protein tyrosinekinase activity in a mammal by administration of a therapeuticallyeffective amount of at least one compound of Formula I.

Examples of compounds of Formula I are:

-   5-Cyano-furan-2-carboxylic acid    (4-morpholin-4-yl-2-piperidin-1-yl-phenyl)-amide;-   5-Cyano-furan-2-carboxylic acid    [4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide-   5-Cyano-furan-2-carboxylic acid    (2-piperidin-1-yl-4-thiomorpholin-4-yl-phenyl)-amide;-   5-Cyano-furan-2-carboxylic acid    [4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-2-piperidin-1-yl-phenyl]-amide;-   5-Cyano-furan-2-carboxylic acid    [4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-2-piperidin-1-yl-phenyl]-amide;-   5-Cyano-furan-2-carboxylic acid    [5-chloro-4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide;-   5-Cyano-furan-2-carboxylic acid    [5-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide;-   5-Cyano-furan-2-carboxylic acid    (5-morpholin-4-yl-2-piperidin-1-yl-phenyl)-amide;-   5-Cyano-furan-2-carboxylic acid    [2-(4-methyl-piperidin-1-yl)-4-morpholin-4-yl-phenyl]-amide;-   5-Cyano-furan-2-carboxylic acid    [4-(4-methyl-piperazin-1-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide;-   4-[4-[(5-Cyano-furan-2-carbonyl)-amino]-3-(4-methyl-piperidin-1-yl)-phenyl]-piperazine-1-carboxylic    acid benzyl ester;-   4-[4-[(5-Cyano-furan-2-carbonyl)-amino]-3-(4-methyl-piperidin-1-yl)-phenyl]-piperazine-1-carboxylic    acid tert-butyl ester;-   5-Cyano-furan-2-carboxylic acid    [2-(4-methyl-piperidin-1-yl)-4-piperazin-1-yl-phenyl]-amide    tris(trifluoroacetic acid salt);-   5-Cyano-furan-2-carboxylic acid    [4-(4-acetyl-piperazin-1-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide;-   5-Cyano-furan-2-carboxylic acid    [4-(4-methanesulfonyl-piperazin-1-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide;-   Carbonic acid tert-butyl ester    2-{4-[4-[(5-cyano-furan-2-carbonyl)-amino]-3-(4-methyl-piperidin-1-yl)-phenyl]-piperazin-1-yl}-ethyl    ester;-   5-Cyano-furan-2-carboxylic acid    [4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-2-(4-methyl-piperidin-1-yl)-phenyl]-amide    trifluoroacetic acid salt;-   5-Cyano-furan-2-carboxylic acid    [5-fluoro-4-(4-methyl-piperazin-1-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide;-   5-Cyano-furan-2-carboxylic acid    (4-azido-2-piperidin-1-yl-phenyl)-amide;-   5-(N-Hydroxycarbamimidoyl)-furan-2-carboxylic acid    (2,4-di-piperidin-1-yl-phenyl)-amide;-   5-Cyano-furan-2-carboxylic acid    [4-(4-methyl-pyrazol-1-yl)-2-piperidin-1-yl-phenyl]-amide;-   4-Methyl-piperazine-1-carboxylic acid    {4-[(5-cyano-furan-2-carbonyl)-amino]-3-piperidin-1-yl-phenyl}-methyl-amide;-   5-Cyano-furan-2-carboxylic acid    [4-(methanesulfonyl-methyl-amino)-2-piperidin-1-yl-phenyl]-amide-   Acetic acid    {4-[(5-cyano-furan-2-carbonyl)-amino]-3-piperidin-1-yl-phenylcarbamoyl}-methyl    ester;-   5-Cyano-furan-2-carboxylic acid    (4-methanesulfonylamino-2-piperidin-1-yl-phenyl)-amide;-   5-Cyano-furan-2-carboxylic acid    [4-methyl-6′-(4-methyl-piperidin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]-bipyrazinyl-5′-yl]-amide;-   5-Cyano furan-2-carboxylic acid    [4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide    hydrochloride;-   4-[4-[(5-Cyano-furan-2-carbonyl)-amino]-3-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-piperazine-1-carboxylic    acid tert-butyl ester;-   4-[4-(4-Methyl-piperazin-1-yl)-2-piperidin-1-yl-phenylcarbamoyl]-oxazole-2-carboxylic    acid methyl ester;-   5-Cyano-furan-2-carboxylic acid    [2-(4-methyl-piperidin-1-yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide    dihydrochloride;-   5-Cyano-furan-2-carboxylic acid    [2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amide    bis(trifluoracetic acid salt);-   4-Cyano-1H-pyrrole-2-carboxylic acid    [2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amide    bis(trifluoracetic acid salt);-   5-Cyano-furan-2-carboxylic acid    [4-(1-acetyl-piperidin-4-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide;-   5-Cyano-1H-imidazole-2-carboxylic acid    [4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide    trifluoroacetic acid salt;-   3H-Imidazole-4-carboxylic acid    [4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide    bis(trifluoroacetic acid salt);-   1H-Imidazole-2-carboxylic acid    [4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide    bis(trifluoroacetic acid salt);-   3H-Imidazole-2,4-dicarboxylic acid 2-amide    4-{[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide}trifluoroacetic    acid salt;-   1H-Imidazole-2-carboxylic acid    [3-chloro-4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide    bis(trifluoroacetic acid salt);-   4-[4-[2-(4-Cyano-1H-pyrrol-2-yl)-2-oxo-ethyl]-3-(4-methyl-piperidin-1-yl)-phenyl]-piperidine-1-carboxylic    acid (2-dimethylamino-ethyl)-amide;-   4-Cyano-1H-pyrrole-2-carboxylic acid    [4-[1-(imidazole-1-carbonyl)-piperidin-4-yl]-2-(4-methyl-piperidin-1-yl)-phenyl]-amide;-   4-Cyano-1H-pyrrole-2-carboxylic acid    {2-(4-methyl-piperidin-1-yl)-4-[1-(pyridine-3-carbonyl)-piperidin-4-yl]-phenyl}-amide;-   4-Cyano-1H-pyrrole-2-carboxylic acid    [4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-2-(4-methyl-piperidin-1-yl)-phenyl]-amide;-   4-Cyano-1H-pyrrole-2-carboxylic acid    {2-(4-methyl-piperidin-1-yl)-4-[1-(2,2,2-trifluoroethyl)-piperidin-4-yl]-phenyl}-amide;-   4-Cyano-1H-imidazole-2-carboxylic acid    [4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide;-   4-[4-[(4-Cyano-1H-pyrrole-2-carbonyl)-amino]-3-(4-methyl-piperidin-1-yl)-phenyl]-piperidine-1-carboxylic    acid (2-hydroxy-ethyl)-amide;-   4-Cyano-1H-pyrrole-2-carboxylic acid    {2-(4-methyl-piperidin-1-yl)-4-[1-(morpholin-4-carbonyl)-piperidin-4-yl]-phenyl}-amide;-   4-[4-[(4-Cyano-1H-pyrrole-2-carbonyl)-amino]-3-(4-methyl-piperidin-1-yl)-phenyl]-piperidine-1-carboxylic    acid 2-dimethylamino-ethyl ester;-   4-Cyano-1H-pyrrole-2-carboxylic acid    [4-[1-(2-methanesulfonyl-acetyl)-piperidin-4-yl]-2-(4-methyl-piperidin-1-yl)-phenyl]-amide;-   4-Cyano-1H-pyrrole-2-carboxylic acid    [4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide;-   4-Cyano-1H-pyrrole-2-carboxylic acid    [4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide;-   4-Cyano-1H-pyrrole-2-carboxylic acid    [4-(4-methyl-piperazin-1-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide;-   5-Cyano-furan-2-carboxylic acid    [4-methyl-6′-(4-methyl-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-amide;-   4-Cyano-1H-pyrrole-2-carboxylic acid    [2-(4-methyl-piperidin-1-yl)-4-piperazin-1-yl-phenyl]-amide    bis(trifluoroacetic acid salt);-   4-Cyano-1H-pyrrole-2-carboxylic acid    [4-(4-acetyl-piperazin-1-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide;-   4-Cyano-1H-pyrrole-2-carboxylic acid    [4-methyl-6′-(4-methyl-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-amide;-   5-Cyano-furan-2-carboxylic    acid[2-(methyl-piperazin-1-yl)-4-(methyl-piperidin-5-yl]-amide    trifluoroacetic acid salt;-   5-Cyano-furan-2-carboxylic    acid[4-methyl-5′-(4-methyl-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-yl]-amide;-   5-Cyano-furan-2-carboxylic    acid[4-methyl-6′-(4-methyl-2-oxo-piperazin-1-yl)-3,4,5,6-tetrahydro-2H—    [1,3′]bipyridinyl-2′-yl]-amide;-   5-Cyano-furan-2-carboxylic    acid[4-methyl-6′-(4-methyl-3-oxo-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-amide;-   5-Cyano-furan-2-carboxylic    acid[4,1″-dimethy-3,4,5,6,1″,2″,3″,4″,5″,6″-decahydro-2H-{1,2′,6′,4″]terpyridin-3′-yl)-amide;-   5-Cyano-furan-2-carboxylic    acid[4-[4-methyl-pierazin-1-yl)-2-morpholin-4-yl-phenyl]-amide;-   5-Cyano-furan-2-carboxylic acid    [4-methyl-6′-(tetrahydro-pyran-4-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-amide;-   5-Cyano-1H-imidazole-2-carboxylic acid    [4-methyl-6′-(tetrahydro-pyran-4-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-amide;-   5-Cyano-furan-2-carboxylic acid    {4-methyl-6′-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl}-amide;-   5-Cyano-furan-2-carboxylic acid    {4-methyl-6′-[4-(2-morpholin-4-yl-acetyl)-piperazin-1-yl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl}-amide    trifluoroacetic acid salt;-   5-Cyano-furan-2-carboxylic acid    [2-(4-fluoro-piperidin-1-yl)-4-(4-methyl-piperazin-1-yl)-phenyl]-amide    trifluoroacetic acid salt; and-   4-Cyano-1H-imidazole-2-carboxylic acid    [2-(3-fluoro-piperidin-1-yl)-4-(4-methyl-piperazin-1-yl)-phenyl]-amine    tris(trifluoroacetic acid salt).

The invention also relates to methods of inhibiting protein tyrosinekinase activity in a mammal by administration of a therapeuticallyeffective amount of at least one compound of Formula I. A preferredtyrosine kinase is c-fms.

The invention is considered to include the enantiomeric, diastereomericand tautomeric forms of all compounds of Formula I as well as theirracemic mixtures. In addition, some of the compounds represented byFormula I may be prodrugs, i.e., derivatives of an acting drug thatpossess superior delivery capabilities and therapeutic value as comparedto the acting drug. Prodrugs are transformed into active drugs by invivo enzymatic or chemical processes.

I. Definitions

The term “alkyl” refers to both linear and branched chain radicals of upto 12 carbon atoms, unless otherwise indicated, and includes, but is notlimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl,octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl.

The term “hydroxyalkyl” refers to both linear and branched chainradicals of up to 6 carbon atoms, in which one hydrogen atom has beenreplaced with an OH group.

The term “hydroxyalkylamine” refers to an hydroxyalkyl group in whichone hydrogen atom from the carbon chain has been replaced with an aminogroup, wherein the nitrogen is the point of attachment to the rest ofthe molecule.

The term “cycloalkyl” refers to a saturated or partially unsaturatedring composed of from 3 to 8 carbon atoms. Up to four alkyl substituentsmay optionally be present on the ring. Examples include cyclopropyl,1,1-dimethyl cyclobutyl, 1,2,3-trimethylcyclopentyl, cyclohexyl andcyclohexenyl.

The term “heterocyclyl” refers to a nonaromatic (i.e. saturated orpartially unsaturated) ring composed of from 3 to 7 carbon atoms and atleast one heteroatom selected from N, O or S. Alkyl substituents mayoptionally be present on the ring. Examples include tetrahydrofuryl,dihydropyranyl, piperidyl, 2,5-dimethypiperidyl, morpholinyl,piperazinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl,pyrazolinyl, imidazolidinyl and imidazolinyl.

The term “dihydrosulfonopyranyl” refers to the following radical:

The term “heterocyclylalkyl” refers to a C₁₋₆ alkyl group containing aheterocyclyl substituent. Examples include dihydropyranylethyl and2-morpholinylpropyl.

The term “hydroxyalkyl” refers to at least one hydroxyl group bonded toany carbon atom along an alkyl chain.

The term “aminoalkyl” refers to at least one primary or secondary aminogroup bonded to any carbon atom along an alkyl chain, wherein an alkylgroup is the point of attachment to the rest of the molecule.

The term “alkylamino” refers to an amino with one or two alkylsubstituents, wherein the amino group is the point of attachment to therest of the molecule.

The term “alkoxyalkyl” refers to at least one alkoxy group bonded to anycarbon atom along an alkyl chain.

The term “polyalkoxyalkyl” refers to long-chain alkoxy compounds andincludes polyethylene glycols of discreet or monodispersed sizes.

The term “thioalkyl” refers to at least one sulfur group bonded to anycarbon atom along an alkyl chain. The sulfur group may be at anyoxidation state and includes sulfoxides, sulfones and sulfates.

The term “carboxyalkyl” refers to at least one carboxylate group bondedto any carbon atom along an alkyl chain. The term “carboxylate group”includes carboxylic acids and alkyl, cycloalkyl, aryl or aralkylcarboxylate esters.

The term “heteroaromatic” or “heteroaryl” refers to 5- to 7-memberedmono- or 8- to 10-membered bicyclic aromatic ring systems, any ring ofwhich may consist of from one to four heteroatoms selected from N, O orS where the nitrogen and sulfur atoms can exist in any allowed oxidationstate. Examples include benzimidazolyl, benzothiazolyl, benzothienyl,benzoxazolyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl,thiazolyl and thienyl.

The term “heteroaralkyl” refers to a C₁₋₆ alkyl group having aheteroaryl substituent. Examples include furylethyl and2-quinolinylpropyl.

The term “heteroatom” refers to a nitrogen atom, an oxygen atom or asulfur atom wherein the nitrogen and sulfur atoms can exist in anyallowed oxidation states.

The term “alkoxy” refers to straight or branched chain radicals of up to12 carbon atoms, unless otherwise indicated, bonded to an oxygen atom.Examples include methoxy, ethoxy, propoxy, isopropoxy and butoxy.

The term “aryl” refers to monocyclic or bicyclic aromatic ring systemscontaining from 6 to 12 carbons in the ring. Alkyl substituents mayoptionally be present on the ring. Examples include benzene, biphenyland napththalene.

The term “aralkyl” refers to a C₁₋₆ alkyl group containing an arylsubstituent. Examples include benzyl, phenylethyl or 2-naphthylmethyl.

The term “heteroaralkyl” refers to a C₁₋₆ alkyl group containing aheteroaryl substituent. Examples include furylmethyl and pyridylpropyl.

The term “aryloxy” refers to an oxygen atom bound to an arylsubstituent. Examples include phenoxy and benzyloxy.

The term “arylalkoxy” refers to an alkoxy group bound to an arylsubstituent. Examples include phenylmethyl ether.

The term “acyl” refers to the group —C(O)R_(a), where R_(a) is alkyl,aryl, aralkyl, heteroaryl and heteroaralkyl. An “acylating agent” addsthe —C(O)R_(a) group to a molecule.

The term “sulfonyl” refers to the group —S(O)₂R_(a), where R_(a) ishydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl andheteroaralkyl. A “sulfonylating agent” adds the —S(O)₂R_(a) group to amolecule.

II. Therapeutic Uses

The compounds of Formula I represent novel potent inhibitors of proteintyrosine kinases, such as c-fms, and may be useful in the prevention andtreatment of disorders resulting from actions of these kinases.

The invention also provides methods of inhibiting, a protein tyrosinekinase comprising contacting the protein tyrosine kinase with aneffective inhibitory amount of at least one of the compounds of FormulaI. A preferred tyrosine kinase is c-fms. The compounds of the presentinvention are also inhibitors of FLT3 tyrosine kinase activity. In oneembodiment of inhibiting a protein tyrosine kinase, at least one of thecompounds of Formula I is combined with a known tyrosine kinaseinhibitor.

In various embodiments of the invention, the protein tyrosine kinasesinhibited by the compounds of Formula I are located in cells, in amammal or in vitro. In the case of mammals, which includes humans, atherapeutically effective amount of a pharmaceutically acceptable formof at least one of the compounds of Formula I is administered.

The invention further provides methods of treating cancer in mammals,including humans, by administration of a therapeutically effectiveamount of a pharmaceutically acceptable composition of least onecompound of Formula I. Exemplary cancers include, but are not limitedto, acute myeloid leukemia, acute lymphocytic leukemia, ovarian cancer,uterine cancer, breast cancer, colon cancer, stomach cancer, hairy cellleukemia and non-small lung carcinoma. The invention also providesmethods of treating certain precancerous lesions includingmyelofibrosis. In one embodiment of the invention, an effective amountof at least one compound of Formula I is administered in combinationwith an effective amount of a chemotherapeutic agent.

The invention further provides methods of treating and of preventingmetastasis arising from cancers that include, but are not limited to,ovarian cancer, uterine cancer, breast cancer, colon cancer, stomachcancer, hairy cell leukemia and non-small lung carcinoma.

The invention further provides methods for the treatment osteoporosis,Paget's disease, and other diseases in which bone resorption mediatesmorbidity including arthritis, prosthesis failure, osteolytic sarcoma,myeloma, and tumor metastasis to bone as occurs frequently in cancersincluding, but not limited to, breast cancer, prostate cancer, and coloncancer.

The invention also provides methods of treating pain, in particularskeletal pain caused by tumor metastasis or osteoarthritis, as well asvisceral, inflammatory, and neurogenic pain.

The invention also provides methods of treating cardiovascular andinflammatory diseases in mammals, including humans, by administration ofa therapeutically effective amount of a pharmaceutically acceptable formof at least one of the compounds of Formula I. Examples of diseases thatmay be effectively treated include atherosclerosis, cardiac hypertrophy,glomerulonephritis, rheumatoid arthritis, psoriasis, diabetes, tumorrelated angiogenesis, restenosis, schizophrenia and Alzheimer'sdementia. These may be effectively treated with compounds of thisinvention. Other diseases that may be effectively treated include, butare not limited to atherosclerosis and cardiac hypertrophy. Autoimmunediseases such as systemic lupus erythematosus, rheumatoid arthritis,Sjogren's syndrome, multiple sclerosis, or uveitis, can also be treatedwith compounds of this invention.

When employed as protein tyrosine kinase inhibitors, the compounds ofthe invention may be administered in an effective amount within thedosage range of about 0.5 mg to about 10 g, preferably between about 0.5mg to about 5 g, in single or divided daily doses. The dosageadministered will be affected by factors such as the route ofadministration, the health, weight and age of the recipient, thefrequency of the treatment and the presence of concurrent and unrelatedtreatments.

The compounds of Formula I may be formulated into pharmaceuticalcompositions comprising any known pharmaceutically acceptable carriers.Exemplary carriers include, but are not limited to, any suitablesolvents, dispersion media, coatings, antibacterial and antifungalagents and isotonic agents. Exemplary excipients that may also becomponents of the formulation include fillers, binders, disintegratingagents and lubricants.

The pharmaceutically-acceptable salts of the compounds of Formula Iinclude the conventional non-toxic salts or the quaternary ammoniumsalts which are formed from inorganic or organic acids or bases.Examples of such acid addition salts include acetate, adipate, benzoate,benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride,hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate,pivalate, propionate, succinate, sulfate and tartrate. Base saltsinclude ammonium salts, alkali metal salts such as sodium and potassiumsalts, alkaline earth metal salts such as calcium and magnesium salts,salts with organic bases such as dicyclohexylamine salts and salts withamino acids such as arginine. Also, the basic nitrogen-containing groupsmay be quaternized with, for example, alkyl halides.

The pharmaceutical compositions of the invention may be administered byany means that accomplish their intended purpose. Examples includeadministration by parenteral, subcutaneous, intravenous, intramuscular,intraperitoneal, transdermal, buccal or ocular routes. Alternatively orconcurrently, administration may be by the oral route. Suitableformulations for parenteral administration include aqueous solutions ofthe active compounds in water-soluble form, for example, water-solublesalts, acidic solutions, alkaline solutions, dextrose-water solutions,isotonic carbohydrate solutions and cyclodextrin inclusion complexes.

III. Methods of Preparation

Scheme 1 illustrates general methodology for the preparation ofcompounds of Formula I.

Compounds of Formula 1-2 can be obtained by nucleophilic aromaticsubstitution on compounds of Formula 1-3 (where L₁ is a leaving groupsuch as a halogen, preferably fluoro or chloro) with amines R₂R₃NHfollowed by reduction of the nitro group. Nucleophilic aromaticdisplacements can be performed in the presence of a suitable base suchas excess R₂R₃NH, NEt₃ or K₂CO₃ in a suitable solvent such as DMF. Nitroreductions can be performed according to standard syntheticmethodologies (for a review, see M. Hudlicky, Reductions in OrganicChemistry, Wiley, N.Y. (1984)) and include preferred methods such aspalladium-catalyzed hydrogenolysis or treatment with iron (0) and NH₄Cl(see, for example, S. Mitsumori, et al, J. Med. Chem., 46: 2436-45(2003)).

Alternatively compounds of Formula 1-2 can be obtained byortho-halogenation (preferably bromination) of amino compounds ofFormula 1-1 followed by metal-catalyzed aminations with R₂R₃NH. (Forreviews, see: S. L. Buchwald, et al, Top. Curr. Chem., 219:131-209(2001) and J. F. Hartwig in “Organopalladium Chemistry for OrganicSynthesis,” Wiley Interscience, NY (2002) and examples therein.)Catalysts suitable for aminations include metal complexes and salts ofpalladium and copper as described below and in the aforementionedreferences. The NH₂ group may be optionally protected prior to thecoupling using a number of protecting groups such as tert-butoxycarbonyl(BOC) (see, for example, M. C. Harris, et al, Org. Lett., 4:2885-8(2002).) (For examples of amine protecting groups and their use, seeTheodora W. Greene and Peter G. M. Wuts, John Wiley and Sons, Inc., NY(1991)). The preferred conditions for bromination are N-bromosuccinimide(NBS) in a suitable solvent such as N,N-dimethylformamide (DMF),dichloromethane (DCM) or acetonitrile. Metal-catalyzed aminations can beperformed according to standard methodology, preferably in the presenceof a palladium catalyst such as Pd₂(dba)₃ or Pd(OAc)₂, a ligand such asBINAP or preferably 2-diphenylphoshino-2′-(N,N-dimethylamino)biphenyl, abase such as Cs₂CO₃, and a suitable solvent such as toluene, dioxane orDME. The protecting group, if present, would then be removed at thispoint using suitable reagents, preferably trifluoroacetic acid in DCM ifthe protecting group was a BOC.

Compounds of Formula 1-4 can be prepared by reaction of compounds ofFormula 1-2 with carboxylic acids WCOOH according to standard proceduresfor amide bond formation (for a review, see: M. Bodansky and A.Bodansky, The Practice of Peptide Synthesis, Springer-Verlag, NY (1984))or by reaction with acid chlorides WCOCl or activated esters WCO₂Rq(where Rq is a leaving group such as pentafluorophenyl orN-succinimide). The preferred reaction conditions for coupling withWCOOH are: when W is a furan, oxalyl chloride in DCM with DMF as acatalyst to form the acid chloride WCOCl and then coupling in thepresence of a trialkylamine such as N,N-diisopropylethylamine (DIEA);when W is a pyrrole, 1-(3-dimethylaminopropyl)-3-carbodiimidehydrochloride (EDCl) and 1-hydroxybenzotriazole (HOBt); and when W is animidazole, the preferred conditions are bromotri(pyrrolidino)phosphoniumhexafluorophosphate (PyBroP) and DIEA in DCM.

It should be understood that the optional substitution present inFormula I may be present in the starting materials 1-1 or 1-3 and, insuch cases, would be carried through the synthesis outlined in Scheme 1.Alternatively various substituents on compounds of Formula I may beintroduced in a number of ways described below to provide the optionalsubstitution listed for Formula I. For example, leaving groups presenton compounds of Formula 1-1 or 1-3, can be substituted before or at anystep during Scheme 1. When such leaving groups (preferably fluoro orchloro) are activated by the nitro group of Formula 1-3 for nucleophilicattack, they can undergo direct nucleophilic aromatic substitution byammonia and azide anion or by amines, alcohols, thiols and othernucleophiles in the presence of a suitable base such as K₂CO₃, DIEA orNEt₃. When the leaving group is suitable for metal-catalyzed couplings(preferably bromo or trifluoromethanesulfonyloxy), a number ofcross-coupling reactions (such as Suzuki or Stille reactions) may beperformed to introduce aryl, heteroaryl, alkenyl or cycloalkenyl groups(for reviews, see N. Miyaura, A. Suzuki, Chem. Rev., 95:2457 (1995), J.K. Stille, Angew. Chem, Int. Ed. Engl., 25: 508024 (1986) and A. Suzukiin Metal-Catalyzed Coupling Reactions, F. Deiderich, P. Stang, Eds.,Wiley-VCH, Weinheim (1988)). Metal-catalyzed cross-couplings (preferablySuzuki reactions using a boronic acid or boronic ester) can be performedaccording to standard methodology, preferably in the presence of apalladium catalyst such as Pd(PPh₃)₄, an aqueous base such aq. Na₂CO₃,and a suitable solvent such as toluene, ethanol, DME, or DMF. Othermetal-catalyzed coupling reactions that can be employed include aromaticand heteroaromatic amination and amidation (for reviews, see referencesfor amination chemistry cited above for conversion of Formulas 1-1 to1-2.)

When the products of a cross-coupling reaction contain an olefin, theolefin can be reduced, if desired, preferably by hydrogenation in thepresence of a catalyst such as palladium on carbon in a suitable solventsuch as methanol or THF, to give the corresponding saturated product.

In some cases, the initial substituents formed can be furtherderivatized as described below to provide the final substitution ofFormula I.

An alternative method to direct substitution to introducenitrogen-containing heterocyclic substituents onto ring A is to form theheterocycle from an aniline amino group on ring A. The aniline aminogroup may be originally present in the starting material in a protectedor unprotected form or may result from the reduction of a nitro groupwhich also can be either originally present in the starting material orattached by a nitration reaction. In addition, the amino group may beformed by reduction of an azide group which can be present in thestarting material or may result from nucleophilic aromatic substitutionof an activated halide by azide anion as mentioned above. The aminogroup may also result from nucleophilic aromatic substitution of anactivated halide (in, for example a nitrohalo compound) by ammonia or bythe anion of a protected ammonia equivalent, for example, t-butylcarbamate. If introduced in protected form, the amine can be deprotectedaccording to standard literature methods. (For examples of amineprotecting groups and deprotection methods see: Theodora W. Greene andPeter G. M. Wuts, John Wiley and Sons, Inc., NY (1991).) Thering-forming reaction involves treatment of the aniline amino group witha suitable optionally substituted di-electrophile, preferably a dihalideor dicarbonyl compound, which results in two substitutions on the aminogroup to form an optionally substituted heterocycle. In the case ofdihalides, any of a number of suitable bases can be added as an acidscavenger such as potassium carbonate, sodium hydroxide, or, atrialkylamine such as triethylamine. Thus, treatment with abis(2-haloethyl)amine such as bis(2-chloroethyl)amine orbis(2-bromoethyl)amine would afford a piperazine ring (see, for example,J. Med. Chem., 29: 640-4 (1986) and J. Med. Chem., 46: 2837 (2003)).Optional substitution on the amine nitrogen of the reagent wouldincorporate optional substitution on the terminal amine of thepiperazine. For example, treatment with N,N-bis(2-chloroethyl)anilinewould give an N-phenylpiperazino group. Treatment with abis(2-haloethyl)ether or bis(2-haloethyl)thioether would afford amorpholine or thiomorpholine ring, respectively. Treatment with anoptionally substituted dihaloalkane such as 1,5-dibromopentane or1,4-dibromobutane would form a piperidine or pyrrolidine, respectively.For example, treatment with 1,5-dibromo-3,3-dimethylpentane would formthe corresponding 3,3-dimethylpiperidino group (see, for example, J.Org. Chem., 50: 2690-8 (1985) and J. Org. Chem., 66: 8127-34 (2001)).Also, treatment with a dihalodialkylketone could provide a carbonylcontaining nitrogen heterocycle. For example, bis(2-bromoethyl)ketonecould afford the 4-piperidone ring, (see, Helv. Chim. Acta, 86: 799-811(2003)). Treatment with a dicarbonyl compound can also provide nitrogenheterocycles. For example, treatment with hexane-2,5-dione can provide a2,5-dimethylpyrrole group (see, Synthesis, 86: 1599 (1998)).

Another alternative method to direct substitution to introduceheterocyclic substituents onto ring A is to form the heterocycle from analdehyde (i.e. from a formyl group on ring A). The formyl group may beoriginally present in the starting material in a protected orunprotected form or may result from or any of a number of formylationreactions known in the literature including a Vilsmeier-Haack reaction(for a review of formylation chemistry, see: G. A. Olah, et al, ChemRev., 87: (1987)) or by para-formylation of nitroaromatics (see: A.Katritsky and L. Xie, Tetrahedron Lett., 37:347-50 (1996)).

Finally it is understood that substituents on compounds of Formula 1-4may be further derivatized to provide compounds of Formula 1-5.Protecting groups on compounds of Formula 1-4 can be removed accordingto standard synthetic methodologies (see Theodora W. Greene and Peter G.M. Wuts, John Wiley and Sons, Inc., NY (1991)) and can be then subjectedto further derivatization. Examples of further derivatization ofcompounds of 1-4 to provide compounds of Formulae 1-5 include, but arenot limited to: when compounds of Formula 1-4 contain a primary orsecondary amine, the amine may be reacted with aldehydes or ketones inthe presence of a reducing agent such as sodium triacetoxyborohydride(see Abdel-Magid reference above) to reductively alkylate the amine;with acid chlorides or carboxylic acids and an amide bond formingreagent as described above to form amides; with sulfonyl chlorides toform sulfonamides; with isocyanates or carbamyl chlorides to form ureas;with aryl or heteroaryl halides in the presence of a palladium catalystas described above (see Buchwald and Hartwig references above) to attacharyl and heteroaryl groups to the amines. In addition, when compounds ofFormulae 1-4 contain an aryl or heteroaryl halide (preferably bromide)or an aryl or heteroaryl trifluoromethanesulfonyloxy group, thesecompounds may be further subjected to metal-catalyzed reactions withboronic acids (for example, Suzuki or Stille couplings as describedabove) to attach aryl, heteroaryl, alkenyl or cycloalkenyl groups, orwith amines, alcohols or thiols (Buchwald- or Hartwig-type couplings,see Buchwald and Hartwig references above) to attach various amino,alkoxy, aryloxy, alkylthio or arylthio groups. When compounds of Formula1-4 contain a cyano group, this group may be hydrolyzed to amides oracids under acid or basic conditions. The resulting acids may thecoupled to amines to form amides using the methology described above.Basic amines may be oxidized to N-oxides and conversely N-oxides may bereduced to basic amines. When compounds of Formula 1-4 contain asulfide, either acyclic or cyclic, the sulfide can be further oxidizedto the corresponding sulfoxides or sulfones. Sulfoxides can be obtainedby oxidation using an appropriate oxidant such as one equivalent ofMCPBA or by treatment with NaIO₄ (see, for example, J. Regan, et al, J.Med. Chem., 46: 4676-86 (2003)) and sulfones can be obtained using twoequivalents of MCPBA or by treatment with 4-methylmorpholine N-oxide andcatalytic osmium tetroxide (see, for example, PCT application WO01/47919).

Scheme 2a illustrates a route to compounds when (Z=CH) where Erepresents —NQR₃—, —O-(D₁=D₂=H), —S-(D₁=D₂=H), —SO-(D₁=D₂=H), or—SO₂-(D₁=D₂=H). Ketones of formula 2-1 can be converted to a vinyltriflate of formula 2-2 by treatment with a non-nucleophilic base suchas LDA and then trapping of the resulting enolate with a triflatingreagent such as trifluoromethanesulfonic anhydride or preferablyN-phenyltrifluoromethanesulfonimide. Suzuki coupling of boronic acids orboronate esters of formula 2-3 (prepared by palladium catalyzedborylation, see for example J. Org. Chem., 60: 7508 (1995)), to vinyltriflates of formula 2-2 provide compounds of formula 2-4 (see, forexample, Synthesis, 993 (1991)). Compounds of Formula 2-4 where E=—SO—or —SO₂— are obtained by oxidation of compounds of Formula 2-4 whereE=—S— with a reagent such as MCPBA (one equivalent for E=—SO—, twoequivalents for E=—SO₂—) or by other methods as described in Scheme 1.

Compounds of formula 2-5 are obtained by reduction of the olefin andnitro group with Pd/C. Following the methods described in Scheme 1,compounds of formula 2-5 are then converted by amide bond formation intocompounds of formula 2-6, which also represent compounds of Formula I ifno further substitution or modification is required.

Compounds of formula 2-6 may be further modified to provide additionalcompounds of Formula I. For example, in cases where E is —NQR₃—, Q=adirect bond, and R₃ represents a BOC protecting group (CO₂t-Bu), the BOCgroup may be removed according to standard methodology such astrifluoroacetic acid (TFA) in DCM (Greene and Wuts, ibid.) to provide asecondary amine that can then be further derivatized to providecompounds of Formula I. Further derivatization includes, but is notlimited to: reactions with aldehydes or ketones in the presence of areducing agent such as sodium triacetoxyborohydride to provide compoundsof Formula I where E=—NCH₂R₃ (see Abdel-Magid J. Org. Chem. 61, pp.3849-3862, (1996)); with acid chlorides or with carboxylic acids and anamide bond forming reagent (as described in Scheme 1) to providecompounds of Formula I where E=—NCOR₃; with sulfonyl chlorides (asdescribed in Scheme 1) to provide compounds of Formula I whereE=—NSO₂R_(a); with isocyanates (as described in Scheme 1) to providecompounds of Formula I where E=—NCONR_(a)R_(b); or subjected tometal-catalyzed substitution reactions as outlined in Scheme 1 toprovide compounds of Formula I where E=—NR₃. (S. L. Buchwald, et al,ibid.; J. H. Hartwig, ibid.)

Scheme 2b illustrates a modification of Scheme 2a to synthesizecompounds of Formula I. E represents —NQR₃—, —O-(D₁=D₂=H), —S-(D₁=D₂=H),—SO-(D₁=D₂=H), or —SO₂-(D₁=D₂=H). Compounds of formula 2-4 are preparedas shown in Scheme 2a. Compounds of formula 2-7 are obtained by NO₂group reduction by a method that does not reduce olefins such as ironand ammonium chloride (as described in Scheme 1). Compounds of Formula Iare then obtained as described in Scheme 1 and Scheme 2a.

Scheme 3 illustrates the preparation of intermediates for the synthesisof compounds of Formula I, where ring A is a 6-membered heterocycle,R₁═H, and R₄ is the optional substitution on ring A or one of theheterocyclic substituents as defined above. At least one of the J₁, J₂and J₃ in Formula 3-1 is N and the remainder are N or C—R (R is H,halogen, CN, C1-C₆ alkyl, C₁-C₄ alkoxy, CF₃, aralkyl, heteroarylkyl,aryl, aryloxy, COORa, CONRaRb, as defined supra). K═NH₂ or otherfunctional groups such as NO₂, COOH or COOR which can eventually beconverted to amino group by known literature methods such as reductionsfor NO₂ (as discussed for Scheme 1) or Curtius rearrangement for COOH(for a review, see Organic Reactions, 3: 337 (1947)). L₃ and L₄ arehalogens. (K═COOH can also be formed from K═COOR by simple base- oracid-catalyzed hydrolysis.)

In general, the selectivity and order in introducing R² and R⁵ can beachieved by the relative reactivity of the halogens L³ and L⁴ chosen incompound (3-1), the intrinsic selectivity of the heterocycle and/or thereaction conditions employed. An example of using the relativereactivity of the halogens L³ and L⁴ in selectively introducing R² andR⁵ would include the situation where, in compounds of Formula 3-1 whereL³ is a fluoro group and L⁴ is a bromo group, selective displacement ofthe fluoro group by a nucleophile can be achieved followed bysubstitution of the remaining bromo group by metal-catalyzedsubstitution chemistry (such as Suzuki or Stille cross-couplingreactions as further outlined below). Similarly in compounds of Formula3-1 where one of L³ and L⁴ is an iodo group and the other is a bromo orchloro group, selective metal-catalyzed substitution chemistry (such asSuzuki or Stille cross-coupling reactions or Buchwald/Hartwig aminationsas further discussed below) on the iodo group can be achieved followedby replacement of the remaining bromo or chloro group by anothermetal-catalyzed substitution reaction.

As illustrated in Scheme 3, leaving group L₃ in Formula 3-1 can be firstsubstituted to obtain compounds of Formula 3-3 or leaving group L₄ canbe first substituted to obtain compound of Formula 3-2. Compounds 3-2 or3-3 can then be reacted to displace L₃ or L₄ to furnish the compound ofFormula 3-4.

A direct nucleophilic displacement or metal-catalyzed amination ofcompound of Formula 3-1 with a secondary amine, ammonia or a protectedamine such as tert-butyl carbamate (for review, see Modern AminationMethods: Ricci, A., Ed.; Wiley-VCH: Weinheim, 2000), can be used tointroduce R₂ or R₄ in Formula 3-2 or 3-3 where R₂ or R₄ is a primary orsecondary amine, amino group (NH₂), and amine equivalent or a protectedamino group. Metal-catalyzed coupling of compound 3-1 with boronic acidsor boronates esters (Suzuki reaction, M=boronic acid group or boronateester group) or with organotin compounds (Stille reaction, M=SnR₃, whereR=alkyl and the other substituents as defined above, as described inScheme 1 can provide compounds of Formula 3-2 or 3-3.

Compound 3-2 also can be converted to compound 3-4 by a directnucleophilic displacement or metal-catalyzed amination with a primary orsecondary amine, ammonia or a protected amine such as tert-butylcarbamate as described above. L₄ in compound 3-3 also can be substitutedwith R₄ to obtain compound of Formula 3-4 by a direct nucleophilicsubstitution or metal catalyzed reaction with N nucleophile or bymetal-catalyzed cross-coupling reaction as described above. When R₂ orR₄ in formula (3-2, 3-3 or 3-4) is a protected amine and K not an aminogroup, it can be deprotected to unmask the amino functionality. Thisamino functionality can then be further derivatized as described inScheme 1. When the K group in Formula 3-4 is not an amino group (such asfunctionality described above), it can be converted to an amino groupaccording to known literature methods (see, for example ComprehensiveOrganic Transformations: Larock, R. S.; Wiley and Sons Inc., USA, 1999)and the resulting amine 3-5 can be employed in amide bond formationreactions as described in Scheme (1) to obtain the compounds in FormulaI. When K in Formula 3-4 is an amino group it can be directly used inamide coupling as described above.

Scheme 4 illustrates the preparation of intermediates to be furthermodified according to Scheme 3 starting from a monohalo-substitutedcompound of Formula 4-1 and 4-5 by introducing the second leaving groupafter the replacement of the first one has been completed. These canalso be used for the synthesis of compounds of Formula I where ring A isa 6-membered heterocycle and R₄ is the optional substitution on Ring Aor one of the heterocyclic substituents. As in Scheme 3, at least one ofJ₁, J₂ and J₃ are N and the remainder are N or C—R (R═H, halogen, CN,C₁-C₆ alkyl, et al.). K═NH₂ or other functional groups such as NO₂, COOHor COOR which can eventually be converted to amino group by knownliterature methods such as reductions or Curtius rearrangement asdescribed in Scheme 3. L₃ and L₄ are halogens. In these compounds, T iseither H or a functional group such as OH that can be converted toleaving groups L₃ or L₄ such as halogen, triflate or mesylate by knownliterature methods (see, for example, Nicolai, E., et al., J.Heterocyclic Chemistry, 31, (73), (1994)). Displacement of L₃ incompound of Formula 4-1 or L₄ in Formula 4-5 by methods described inScheme 3, can yield compounds of Formula 4-2 and 4-6. At this point, thesubstituent T of compound 4-2 or 4-6 can be converted to a halogen bystandard methods to provide compounds of Formula 4-3 and 4-5. Forexample, when T=OH, the preferred reagents to effect this transformationare thionyl chloride, PCl₅, POCl₃ or PBr₃ (see, for examples, Kolder,den Hertog., Recl. Trav. Chim. Pays-Bas; 285, (1953), Iddon, B, et. Al.,J. Chem. Soc. Perkin Trans. 1., 1370, (1980)). When T=H, it can bedirectly halogenated (preferably brominated) to provide compounds offormula 4-3 or 4-7 (see, for example, Canibano, V. et al., Synthesis,14, 2175, (2001)). The preferred conditions for bromination are NBS in asuitable solvent such as DCM or acetonitrile.

The compounds of Formulae 4-3 or 4-7 can be converted to compounds ofFormulae 4-4 or 4-8 by introduction of the remaining groups R₂ or R₄respectively, as described above and then on to compounds of Formula I,by the methods described in Scheme 3 for conversion of compounds ofFormulae 3-2 and 3-3 to compounds of Formula I.

This invention is illustrated by the following examples.

Example 1 5-Cyano-furan-2-carboxylic acid

To 2.8 g of 2-formyl-5-furancarboxylic acid (20 mmol) and 2.7 g ofhydroxylamine hydrochloride (40 mmol) under Ar was added and drypyridine (50 mL). The mixture was heated to 85° C., acetic anhydride (40mL) was added and the mixture was stirred for 3 h. After cooling to 60°C., water (250 mL) was added and the mixture was stirred at RT for 70 h.The mixture was acidified to pH 2 with concentrated hydrochloric acidand extracted with 3:1 dichloromethane-isopropanol (8×100 mL). Thecombined organic layers were washed with water (100 mL), brine (100 mL),dried over anh sodium sulfate and concentrated in vacuo to afford thetitle compound as a tan solid (1.26 g, 46%). ¹H-NMR (CD₃OD; 400 MHz): δ14.05 (br s, 1H), 7.74 (d, OH, J=3.8 Hz), 7.42 (d, 1H, J=3.8 Hz).

Example 2 4-Cyano-1H-pyrrole-2-carboxylic acid

The title compound was prepared by the literature procedure (Loader andAnderson, Canadian J. Chem., 59: 2673 (1981)).

Example 34-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt

a) 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile

A flask charged with imidazole-4-carbonitrile (0.50 g, 5.2 mmol)(Synthesis, 677 (2003)) 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl)(0.95 mL, 5.3 mmol), K₂CO₃ (1.40 g, 10.4 mmol), and acetone (5 mL) wasstirred for 10 h at RT. The mixture was diluted with EtOAc (20 mL) andwashed with water (20 mL) and brine (20 mL) and the organic layer driedover MgSO₄. The crude product was eluted from a 20-g SPE cartridge(silica) with 30% EtOAc/hexane to give 0.80 g (70%) of the titlecompound as a colorless oil. Mass spectrum (CI(CH₄), m/z) Calcd. forC₁₀H₁₇N₃OSi, 224.1 (M+H), found 224.1.

b)2-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile

To a solution of1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile (0.70 g,3.1 mmol) (as prepared in the previous step) in CCl₄ (10 mL) was addedNBS (0.61 g, 3.4 mmol) and AIBN (2 mg, catalytic), and the mixtureheated at 60° C. for 4 h. The reaction was diluted with EtOAc (30 mL)and washed with NaHCO₃ (2×30 mL) and brine (30 mL) and the organic layerwas dried over Na₂SO₄ and then concentrated. The title compound waseluted from a 20-g SPE cartridge (silica) with 30% EtOAc/hexane to give0.73 g (77%) of a yellow solid. Mass spectrum (CI(CH₄), m/z) Calcd. forC₁₀H₁₆BrN₃OSi, 302.0/304.0 (M+H), found 302.1/304.1.

c) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester

To a solution of2-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile(0.55 g, 1.8 mmol) (as prepared in the previous step) in THF (6 mL) at−40° C. was added drop wise a solution of 2M i-PrMgCl in THF (1 mL). Thereaction was allowed to stir for 10 min at −40° C. and then cooled to−78° C., and ethyl cyanoformate (0.3 g, 3.0 mmol) was added. Thereaction allowed to attain RT and stirred for 1 h. The reaction wasquenched with satd aq NH₄Cl, diluted with EtOAc (20 mL) and washed withbrine (2×20 mL), and the organic layer was dried over Na₂SO₄ and thenconcentrated. The title compound was eluted from a 20-g SPE cartridge(silica) with 30% EtOAc/hexane to give 0.40 g (74%) of a colorless oil.Mass spectrum (ESI, m/z): Calcd. for C₁₃H₂₁N₃O₃Si, 296.1 (M+H), found296.1.

d)4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester (0.40 g, 1.3 mmol) (as prepared in the previous step)in ethanol (3 mL) was added a solution of 6M KOH (0.20 mL) and thereaction was stirred for 10 min and then concentrated to give 0.40 g(100%) of the title compound as a yellow solid. ¹H-NMR (400 MHz, CD₃OD)δ 7.98 (s, 1H), 5.92 (s, 2H), 3.62 (m, 2H), 0.94 (m, 2H), 0.00 (s, 9H).Mass spectrum (ESI-neg, m/z) Calcd. for C₁₁H₁₇N₃O₃Si, 266.1 (M−H), found266.0.

Example 4 5-Cyano-furan-2-carboxylic acid(4-morpholin-4-yl-2-piperidin-1-yl-phenyl)-amide

a) 1-(5-Chloro-2-nitro-phenyl)-piperidine

To a cooled (0° C.) solution of 1.75 g (10.0 mmol) of4-chloro-2-fluoronitrobenzene in 15 mL of EtOH was added 2.97 mL (30.0mmol) of piperidine dropwise over 5 min. The solution stirred at 0° C.for 10 min and then at 23° C. for 30 min. The mixture was poured intowater (225 mL) and extracted with EtOAc (2×30 mL). The combined extractswere washed with saturated aq NaHCO₃ and brine (30 mL each) and thendried (Na₂SO₄) Concentration afforded 2.33 g (97%) of the title compoundas an orange oil which crystallized on standing: Mass spectrum (ESI,m/z): Calcd. for C₁₁H₁₃ClN₂O₂, 241.1 (M+H), found 241.1.

b) 4-(4-Nitro-3-piperidin-1-yl-phenyl)-morpholine

A mixture of 150 mg (0.623 mmol) 1-(5-chloro-2-nitro-phenyl)-piperidine(as prepared in the previous step) and 272 μL (3.12 mmol) of morpholinewere heated with stirring under Ar at 125° C. for 84 h. After cooling tort, the mixture was poured into water (40 mL) and extracted with EtOAc(2×20 mL). The combined extracts were washed with water (2×10 mL) andbrine (10 mL) and then dried (Na₂SO₄) Concentration afforded 162 mg(89%) of the title compound as an orange resin: Mass spectrum (ESI,m/z): Calcd. for C₁₅H₂₁N₃O₃, 292.2 (M+H), found 292.1.

c) 5-Cyano-furan-2-carboxylic acid(4-morpholin-4-yl-2-piperidin-1-yl-phenyl)-amide

A mixture of 38.8 mg (0.131 mmol)4-(4-nitro-3-piperidin-1-yl-phenyl)-morpholine (as prepared in theprevious step) and 38 mg of 10% palladium on carbon (Degussa typeE101-NE/W, Aldrich, 50% by weight water) in 2 mL of THF was stirredvigorously under a balloon of hydrogen for 1 h. The mixture was filtered(Celite) washing with dichloromethane (2×1 mL) and the solution of theresulting aniline was placed under Ar and used immediately in thefollowing reaction.

Simultaneously to the above reduction, 18.0 mg (0.131 mmol) of5-cyanofuran-2-carboxylic acid (as prepared in Example 1) in 1.5 mL ofanh dichloromethane under a CaSO₄ drying tube was treated with 22.9 μL(0.262 mmol) of oxalyl chloride followed by 10 μL of anh DMF. Thesolution was stirred for 1 h and quickly concentrated in vacuo at 25° C.or less. The resulting 5-cyanofuran-2-carbonyl chloride was placed underhigh vacuum for only 2-3 min and then immediately placed under Ar,cooled to 0° C. in an ice bath, and treated with the aniline solutionproduced above followed by 34.3 μL (0.197 mmol) ofN,N-diisopropylethylamine (DIEA). After stirring 30 min at RT, themixture was concentrated in vacuo and the resulting residue flashchromatographed on a 5-g silica SPE column with 20% EtOAc-hexane toafford 38.8 mg (78%) of the title compound as a yellow solid: ¹H-NMR(CDCl₃; 400 MHz): δ 9.53 (br s, 1H), 8.33 (d, 1H, J=8.9 Hz), 7.26 (d,1H, J=3.7 Hz, partially obscured by CHCl₃ peak), 7.22 (d, 1H, J=3.7 Hz),6.78 (d, 1H, J=2.7 Hz), 6.71 (dd, 1H, J=8.9, 2.7 Hz), 3.87 (m, 4H), 3.14(m, 4H), 2.85 (m, 4H), 1.81 (m, 4H), and 1.65 (br m, 2H). Mass spectrum(ESI, m/z): Calcd. for C₂₁H₂₄N₄O₃, 381.2 (M+H), found 381.2.

Example 5 5-Cyano-furan-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide

a) 1-Methyl-4-(4-nitro-3-piperidin-1-yl-phenyl)-piperazine

A mixture of 350 mg (1.45 mmol) of1-(5-chloro-2-nitro-phenyl)-piperidine (as prepared in Example 4, step(a)) and 482 μL (4.35 mmol) of 1-methylpiperazine was heated in a sealedvial at 138° C. for 30 h. The mixture was cooled and poured into 60 mLof water and extracted with EtOAc (2×20 mL). The combined extracts werewashed with brine (30 mL), dried (Na₂SO₄) and concentrated in vacuo toafford 436 mg (99%) of the title compound as a yellow resin: Massspectrum (ESI, m/z): Calcd. for C₁₆H₂₄N₄O₂, 305.2 (M+H), found 305.2.

b) 5-Cyano-furan-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide

The procedure of Example 4, step (c) was followed using 304 mg (1.00mmol) 1-methyl-4-(4-nitro-3-piperidin-1-yl-phenyl)-piperazine (asprepared in the previous step) and 304 mg of 10% palladium on carbon(50% by weight water) to prepare the intermediate aniline(4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenylamine) along with140 mg (1.02 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared inExample 1), 178 μL (2.04 mmol) of oxalyl chloride, 10 μL of anh DMF, and267 μL (1.53 mmol) of DIEA to perform the amide coupling. The resultingresidue was chromatographed on a 20-g silica SPE column with 2-5%EtOH-dichloromethane to afford, after slow concentration fromEtOAc-hexane (1:1), 232 mg (59%) of the title compound as a yellowsolid: ¹H-NMR (CDCl₃; 400 MHz): δ 9.53 (br s, 1H), 8.32 (d, 1H, J=8.9Hz), 7.25 (d, 1H, J=3.7 Hz, partially obscured by CHCl₃ peak), 7.21 (d,1H, J=3.7 Hz), 6.80 (d, 1H, J=2.7 Hz), 6.73 (dd, 1H, J=8.9, 2.7 Hz),3.20 (m, 4H), 2.85 (m, 4H), 2.59 (m, 4H), 2.36 (s, 3H), 1.80 (m, 4H),and 1.65 (br m, 2H). Mass spectrum (ESI, m/z): Calcd. for C₂₂H₂₇N₅O₂,394.2 (M+H), found 394.2.

Example 6 5-Cyano-furan-2-carboxylic acid(2-piperidin-1-yl-4-thiomorpholin-4-yl-phenyl)-amide

a) 4-(4-Nitro-3-piperidin-1-yl-phenyl)-morpholine

A mixture of 172 mg (0.715 mmol) 1-(5-chloro-2-nitro-phenyl)-piperidine(as prepared in Example 4, step (a)) and 360 μL (3.58 mmol) ofthiomorpholine were heated with stirring under Ar at 140° C. for 40 h.After cooling to RT, the mixture was poured into water (50 mL) andextracted with EtOAc (2×20 mL). The combined extracts were washed withwater (3×50 mL) and brine (50 mL) and then dried (Na₂SO₄). Concentrationand chromatography on a 10-g silica SPE column with 60%dichloromethane-hexane afforded 145 mg (66%) of the title compound as ayellow resin: Mass spectrum (ESI, m/z): Calcd. for C₁₅H₂₁N₃O₂S, 308.1(M+H), found 308.1.

b) 5-Cyano-furan-2-carboxylic acid(2-piperidin-1-yl-4-thiomorpholin-4-yl-phenyl)-amide

The title compound was prepared following the procedure of Example 4,step (c) using 86.4 mg (0.281 mmol) of4-(4-nitro-3-piperidin-1-yl-phenyl)-morpholine (as prepared in theprevious step), 86.4 mg of 10% palladium on carbon (50% by weightwater), 38.5 mg (0.281 mmol) of 5-cyanofuran-2-carboxylic acid (asprepared in Example 1), 49.0 μL (0.562 mmol) of oxalyl chloride, and73.5 μL (0.422 mmol) of DIEA. The resulting residue was chromatographedon a 10-g silica SPE column with 10% EtOAc-hexane to afford 75.3 mg(68%) of the title compound as a light yellow crystalline solid: ¹H-NMR(CDCl₃; 400 MHz): δ 9.52 (br s, 1H), 8.31 (d, 1H, J=8.9 Hz), 7.26 (d,1H, J=3.7 Hz, partially obscured by CHCl₃ peak), 7.22 (d, 1H, J=3.7 Hz),6.76 (d, 1H, J=2.7 Hz), 6.70 (dd, 1H, J=8.9, 2.7 Hz), 3.49 (m, 4H), 2.84(m, 4H), 2.77 (m, 4H), 1.81 (m, 4H), and 1.65 (br m, 2H). Mass spectrum(ESI, m/z): Calcd. for C₂₁H₂₄N₄O₂S, 397.2 (M+H), found 397.1.

Example 7 5-Cyano-furan-2-carboxylic acid[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-2-piperidin-1-yl-phenyl]-amide

To a solution of 25.3 mg (0.0638 mmol) 5-cyano-furan-2-carboxylic acid(2-piperidin-1-yl-4-thiomorpholin-4-yl-phenyl)-amide (as prepared inExample 6, step (b)) in 2 mL of MeOH-MeCN (1:1) was added 15.0 mg(0.0702 mmol) of sodium periodate in 0.20 mL of water. After stirringfor 1.5 h, an additional 4.1 mg (0.019 mmol) of sodium periodate wasadded. After stirring for 1.5 h, a final 9.5 mg (0.11 mmol) of sodiumperiodate was added and the mixture stirred for 24 h. The mixture wasconcentrated to near dryness, extracted with EtOAc (10 mL) and dried(Na₂SO₄). Concentration and chromatography on a 5-g silica SPE columnwith a gradient of 60-100% EtOAc-dichloromethane afforded 13.3 mg (51%)of the title compound as a light yellow solid: ¹H-NMR (CDCl₃; 400 MHz):δ 9.51 (br s, 1H), 8.35 (d, 1H, J=8.9 Hz), ca. 7.2 (d, 1H, obscured byCHCl₃ peak), 7.23 (d, 1H, J=3.7 Hz), 6.81 (d, 1H, J=2.6 Hz), 6.77 (dd,1H, J=8.9, 2.6 Hz), 3.94 (m, 2H), 3.51 (m, 2H), 2.91 (m, 4H), 2.85 (m,4H), 1.81 (m, 4H), and 1.66 (br m, 2H). Mass spectrum (ESI, m/z): Calcd.for C₂₁H₂₄N₄O₃S, 413.2 (M+H), found 413.1.

Example 8 5-Cyano-furan-2-carboxylic acid[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-2-piperidin-1-yl-phenyl]-amide

To a solution of 21.5 mg (0.0542 mmol) 5-cyano-furan-2-carboxylic acid(2-piperidin-1-yl-4-thiomorpholin-4-yl-phenyl)-amide (as prepared inExample 6, step (b)) in 0.6 mL of acetone-water (3:1) was added 22.0 mg(0.163 mmol) of 4-methyl-morpholine N-oxide followed by 25 μL (0.0039mmol) of a solution of osmium tetroxide (4.0 wt % in water). Afterstirring for 18 h at RT, 3 mL of water was added and the mixtureextracted with EtOAc (2×5 mL). The combined extracts were washed withbrine (5 mL), dried (Na₂SO₄) and concentrated. Chromatography of theresulting residue on a 5-g silica SPE column with 5-6%EtOAc-dichloromethane afforded 19.1 mg (82%) of the title compound as alight yellow solid: ¹H-NMR (CDCl₃; 400 MHz): δ 9.48 (br s, 1H), 8.36 (d,1H, J=8.9 Hz), ca. 7.28 (d, 1H, J=3.7 Hz), 7.23 (d, 1H, J=3.7 Hz), 6.77(d, 1H, J=2.7 Hz), 6.73 (dd, 1H, J=8.9, 2.7 Hz), 3.80 (m, 4H), 3.14 (m,4H), 2.84 (m, 4H), 1.82 (m, 4H), and 1.67 (br m, 2H). Mass spectrum(ESI, m/z): Calcd. for C₂₁H₂₄N₄O₄S, 429.2 (M+H), found 429.1.

Example 9 5-Cyano-furan-2-carboxylic acid[5-chloro-4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide

a) 1-(4,5-Dichloro-2-nitro-phenyl)-piperidine

The procedure of Example 4, step (a) was followed using 2.10 g (10 mmol)of 1,2-dichloro-4-fluoronitrobenzene and 2.97 mL (30 mmol) of piperidinein 4 mL of EtOH except the reaction was stirred at RT for 4 h.Crystallization from hexane afforded 2.73 g (99%) of the title compoundas a yellow-orange solid: Mass spectrum (ESI, ml/z): Calcd. forC₁₁H₁₂Cl₂N₂O₂, 275.0 (M+H), found 275.0.

b) 1-(2-Chloro-4-nitro-5-piperidin-1-yl-phenyl)-4-methyl-piperazine

The procedure of Example 5, step (b) was followed using 968 mg (3.52mmol) of 1-(4,5-dichloro-2-nitro-phenyl)-piperidine (as prepared in theprevious step) and 1.95 mL (17.6 mmol) of 1-methylpiperazine.Crystallization from hexane afforded 997 mg (84%) of the title compoundas a yellow-tan solid: Mass spectrum (ESI, m/z): Calcd. forC₁₆H₂₃ClN₄O₂, 339.2 (M+H), found 339.1.

c) 5-Cyano-furan-2-carboxylic acid[5-chloro-4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide

To 56.0 mg (0.165 mmol) of1-(2-chloro-4-nitro-5-piperidin-1-yl-phenyl)-4-methyl-piperazine (asprepared in the previous step) in 3 mL of EtOH-water (2:1) was added46.1 mg (0.825 mmol) of iron powder and 88.3 mg (1.65 mmol) of NH₄Cl andthe mixture refluxed under Ar for 15 h. The mixture was poured intoEtOAc (6 mL), filtered (Celite) washing with EtOAc (2×2 mL),concentrated in vacuo and dissolved in anh THF (2 mL). The resultinganiline solution was placed under Ar and used immediately in thefollowing reaction.

To 25.0 mg (0.182 mmol) of 5-cyanofuran-2-carboxylic acid (as preparedin Example 1) in 1.5 mL of anh dichloromethane under a CaSO₄ drying tubewas added 23.8 μL (0.273 mmol) of oxalyl chloride followed by 5 μL ofanh DMF. The solution was stirred for 25 min and then quicklyconcentrated in vacuo at 20-25° C. The residue was placed under highvacuum for only 2-3 min and then immediately placed under Ar, cooled to0° C. in an ice bath, and treated with the aniline solution producedabove followed by 60.4 μL (0.347 mmol) of DIEA. After stirring at RT for30 min, the mixture was concentrated in vacuo and the resulting residuechromatographed on a 10-g silica SPE column with 1-3%EtOH-dichloromethane to afford 46.2 mg (65%) of the title compound as alight yellow solid: ¹H-NMR (CDCl₃; 400 MHz): δ 9.52 (br s, 1H), 8.49 (s,1H), 7.23, 7.28 (AB q, 2H, J=3.7 Hz), 6.89 (s, 1H), 3.0-3.2 (br m, 4H),2.82-2.84 (m, 4H), 2.6-2.7 (br m, 4H), 2.37 (s, 3H), 1.78-1.83 (m, 4H),and 1.6-1.7 (br m, 2H). Mass spectrum (ESI, m/z): Calcd. forC₂₂H₂₆ClN₅O₂, 428.2 (M+H), found 428.1.

Example 10 5-Cyano-furan-2-carboxylic acid[5-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide

a) 3-Nitro-4-piperidin-1-yl-phenylamine

A solution of 1.00 g (6.41 mmol) of 4-fluoro-3-nitroaniline and 3.17 mL(32.1 mmol) of piperidine in 15 mL of acetonitrile under Ar was heatedto reflux for 2 h. The mixture was cooled to RT, concentrated in vacuo,dissolved in EtOAc (60 mL) and washed with 1 M NaOH (2×50 mL), water (50mL), brine (50 mL), and then dried (Na₂SO₄). Concentration afforded 1.40g (99%) of the title compound as dark red crystals: ¹H-NMR (CDCl₃; 400MHz): δ 7.04 (d, 1H, J=8.6 Hz), 7.03 (d, 1H, J=2.8 Hz), 6.81 (dd, 1H,J=8.6, 2.8 Hz), 2.85-2.88 (m, 4H), 1.65-1.70 (m, 4H), and 1.51-1.55 (m,2H).

b) 1-Methyl-4-(3-nitro-4-piperidin-1-yl-phenyl)-piperazine

To a solution of 512 mg g (2.31 mmol) of3-nitro-4-piperidin-1-yl-phenylamine (as prepared in the previous step)and 404 mg (2.10 mmol) of mechlorethamine hydrochloride in 15 mL of EtOHwas added 1.45 g (10.5 mmol) of anh K₂CO₃ and the mixture heated toreflux under Ar for 48 h. The mixture was cooled to RT, concentrated invacuo, extracted with EtOAc (3×20 mL) and the combined extracts filtered(Celite), and concentrated to a dark oil. Chromatography of theresulting residue on a 70-g silica SPE column with a gradient of 0-3%MeOH-dichloromethane afforded 456 mg (71%) of the title compound as adark red solid: Mass spectrum (ESI, m/z): Calcd. for C₁₆H₂₄N₄O₂, 305.2(M+H), found 305.1.

c) 5-Cyano-furan-2-carboxylic acid[5-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide

The title compound was prepared following the procedure of Example 4,step (c) using 28.1 mg (0.0923 mmol) of1-methyl-4-(3-nitro-4-piperidin-1-yl-phenyl)-piperazine (as prepared inthe previous step), 28 mg of 10% palladium on carbon (Degussa typeE101-NE/W, 50% by weight water), 12.7 mg (0.0923 mmol) of5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 16.2 μL(0.185 mmol) of oxalyl chloride, and 24.1 μL (0.138 mmol) of DIEA. Theresulting residue was chromatographed on a 10-g silica SPE column with1-4% MeOH-dichloromethane to afford 25.8 mg (71%) of the title compoundas a beige crystalline solid: ¹H-NMR (CDCl₃; 400 MHz): δ 9.97 (br s,1H), 8.18 (d, 1H, J=2.8 Hz), 7.23, 7.25 (AB q, 2H, J=3.7 Hz), 7.11 (d,1H, J=8.7 Hz), 6.67 (dd, 1H, J=8.7, 2.8 Hz), 3.22-3.25 (m, 4H),2.75-2.85 (m, 4H), 2.56-2.58 (m, 4H), 2.35 (s, 3H), 1.76-1.81 (m, 4H),and 1.5-1.7 (br m, 2H). Mass spectrum (ESI, m/z): Calcd. for C₂₂H₂₇N₅O₂,394.2 (M+H), found 394.2.

Example 11 5-Cyano-furan-2-carboxylic acid(5-morpholin-4-yl-2-piperidin-1-yl-phenyl)-amide

a) 4-(3-Nitro-4-piperidin-1-yl-phenyl)-morpholine

The title compound was prepared following the procedure of Example 10,step (b) using 152 mg (0.687 mmol) of3-nitro-4-piperidin-1-yl-phenylamine (as prepared in Example 10, step(a)), 78.6 mg (0.625 mmol) of 2-bromoethyl ether and 433 mg (3.13 mmol)of anh K₂CO₃ except the mixture was heated to reflux in 2 mL of toluenefor 20 h. Chromatography on a 10-g silica SPE column with 40%Et₂O-hexane afforded 128 mg (70%) of the title compound as a dark orangeresin: Mass spectrum (ESI, m/z): Calcd. for C₁₅H₂₁N₃O₂, 292.2 (M+H),found 292.1.

b) 5-Cyano-furan-2-carboxylic acid(5-morpholin-4-yl-2-piperidin-1-yl-phenyl)-amide

The title compound was prepared following the procedure of Example 5,step (b) using 76.7 mg (0.318 mmol) of4-(3-nitro-4-piperidin-1-yl-phenyl)-morpholine (as prepared in theprevious step), 50 mg of 10% palladium on carbon (50% by weight water),43.6 mg (0.318 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared inExample 1), 55.5 μL (0.636 mmol) of oxalyl chloride, and 83.1 μL (0.477mmol) of DIEA. The resulting residue was chromatographed on a 10-gsilica SPE column with 15-25% EtOAc-hexane to afford 54.9 mg (45%) ofthe title compound as a light yellow solid: ¹H-NMR (CDCl₃; 400 MHz): δ9.97 (br s, 1H), 8.17 (d, 1H, J=2.8 Hz), 7.23, 7.26 (AB q, 2H, J=3.7Hz), 7.13 (d, 1H, J=8.7 Hz), 6.66 (dd, 1H, J=8.7, 2.8 Hz), 3.84-3.87 (m,4H), 23.17-3.19 (m, 4H), 2.75-2.85 (m, 4H), 1.77-1.82 (m, 4H), and1.5-1.7 (br m, 2H). Mass spectrum (ESI, m/z): Calcd. for C₂₁H₂₄N₄O₃,381.2 (M+H), found 381.2.

Example 12 5-Cyano-furan-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-morpholin-4-yl-phenyl]-amide

a) 1-(5-Chloro-2-nitro-phenyl)-4-methyl-piperidine

The procedure of Example 4, step (a) was followed using 0.950 g (5.43mmol) of 4-chloro-2-fluoronitrobenzene and 1.93 mL (16.3 mmol) of4-methylpiperidine in 10 mL of EtOH to afford 1.37 g (99%) of the titlecompound as an orange oil which crystallized on standing: Mass spectrum(ESI, m/z): Calcd. for C₁₂H₁₅ClN₂O₂, 255.1 (M+H), found 255.0.

b) 4-[3-(4-Methyl-piperidin-1-yl)-4-nitro-phenyl]-morpholine

The procedure of Example 4, step (b) was followed using 304 mg (1.19mmol) of 1-(5-chloro-2-nitro-phenyl)-4-methyl-piperidine (as prepared inthe previous step) and 519 μL (5.95 mmol) of morpholine to afford 363 mg(106%) of the title compound as a yellow resin: Mass spectrum (ESI,m/z): Calcd. for C₁₆H₂₃N₃O₃, 306.2 (M+H), found 306.1.

c) 5-Cyano-furan-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-morpholin-4-yl-phenyl]-amide

The procedure of Example 4, step (c) was followed using 101 mg (0.331mmol) of 4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-morpholine (asprepared in the previous step) and 40 mg of 10% palladium on carbon (50%by weight water) in 5 mL THF to prepare the corresponding aniline.However, 5-cyanofuran-2-carboxylic acid N-hydroxysuccinimide ester wasused to acylate the aniline instead of 5-cyanofuran-2-carbonyl chloride.(5-cyanofuran-2-carboxylic acid N-hydroxysuccinimide ester waspreviously prepared from 5-cyanofuran-2-carboxylic acid (as prepared inExample 1), oxalyl chloride, N-hydroxysuccinimide and DIEA following theprocedure of Example 4, step (c).) The aniline prepared above in 3.0 mLof anh dichloromethane was treated with 77.5 mg (0.331 mmol) of5-cyanofuran-2-carboxylic acid N-hydroxysuccinimide ester. Afterstirring for 1 h, an additional 77.5 mg (0.331 mmol) of5-cyanofuran-2-carboxylic acid N-hydroxysuccinimide ester was added.After 3 h, a final 77.5 mg (0.331 mmol) of 5-cyanofuran-2-carboxylicacid N-hydroxysuccinimide ester was added and the mixture stirred 18 h.Concentration in vacuo and chromatography on a 10-g silica SPE columnwith 2-4% EtOAc-dichloromethane afforded 85.1 mg (65%) of the titlecompound as a light yellow solid: ¹H-NMR (CDCl₃; 400 MHz): δ 9.60 (br s,1H), 8.32 (d, 1H, J=8.9 Hz), 7.22, 7.26 (AB q, 2H, J=3.7 Hz), 6.78 (d,1H, J=2.7 Hz), 6.71 (dd, 1H, J=8.9, 2.7 Hz), 3.86-3.88 (m, 4H),3.13-3.15 (m, 4H), 2.98-3.01 (m, 2H), 2.70-2.15 (m, 2H), 1.83-1.86 (m,2H), 1.5-1.7 (br m, 1H) and 1.43-1.53 (m, 2H). Mass spectrum (ESI, m/z):Calcd. for C₂₂H₂₆N₄O₃, 395.2 (M+H), found 395.2.

Example 13 5-Cyano-furan-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide

a) 1-Methyl-4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-piperazine

The procedure of Example 4, step (b) was followed using 150 mg (0.589mmol) of 1-(5-chloro-2-nitro-phenyl)-4-methyl-piperidine (as prepared inthe Example 12, step (a)) and 327 μL (2.95 mmol) of 1-methylpiperazineat 142° C. for 21 h to afford 189 mg (100%) of the title compound as ayellow semisolid: Mass spectrum (ESI, m/z): Calcd. for C₁₆H₂₄N₄O₂, 319.2(M+H), found 319.1.

b) 5-Cyano-furan-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide

The procedure of Example 4, step (c) was followed using 50.2 mg (0.158mmol) of1-methyl-4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-piperazine (asprepared in the previous step), 20 mg of 10% palladium on carbon (50% byweight water), 22.8 mg (0.166 mmol) of 5-cyanofuran-2-carboxylic acid(as prepared in Example 1), 29.0 μL (0.332 mmol) of oxalyl chloride, and57.8 μL (0.332 mmol) of DIEA. Chromatography on a 5-g silica SPE columnwith 0.5-3% MeOH-dichloromethane afforded 34.8 mg (54%) of the titlecompound as a light yellow solid: ¹H-NMR (CDCl₃; 400 MHz): o 9.59 (br s,1H), 8.33 (d, 1H, J=8.9 Hz), 7.21, 7.25 (AB q, 2H, J=3.7 Hz, partiallyobscured by CHCl₃ peak), 6.78 (d, 1H, J=2.7 Hz), 6.74 (dd, 1H, J=8.9,2.7 Hz), 3.35-3.55 (m, 4H), 2.95-3.05 (m, 4H), 2.72-2.75 (m, 4H), 2.67(br s, 3H), 1.83-1.87 (m, 2H), 1.45-1.65 (br m, 1H), 1.43-1.53 (m, 2H)and 1.07 (d, 3H, J=6.2 Hz), Mass spectrum (ESI, m/z): Calcd. forC₂₃H₂₉N₅O₂, 408.2 (M+H), found 408.3.

Example 144-[4-[(5-Cyano-furan-2-carbonyl)-amino]-3-(4-methyl-piperidin-1-yl)-phenyl]-piperazine-1-carboxylicacid benzyl ester

a)4-[3-(4-Methyl-piperidin-1-yl)-4-nitro-phenyl]-piperazine-1-carboxylicacid benzyl ester

The procedure of Example 4, step (b) was followed using 400 mg (1.57mmol) of 1-(5-chloro-2-nitro-phenyl)-4-methyl-piperidine (as prepared inthe Example 12, step (a)) and 910 mg (4.71 mmol) of benzyl1-piperazinecarboxylate (except that 549 μL (4.71 mmol) of 2,6-lutidinewas also added) to afford, after chromatography on a 70-g silica SPEcolumn with 40% EtOAc-hexane, 178 mg (45%) of unreacted1-(5-chloro-2-nitro-phenyl)-4-methyl-piperidine and 245 mg (64% based onrecovered starting material) of the title compound as a yellow resin:Mass spectrum (ESI, m/z): Calcd. for C₂₄H₃₀N₄O₄, 439.2 (M+H), found439.2.

b)4-[4-[(5-Cyano-furan-2-carbonyl)-amino]-3-(4-methyl-piperidin-1-yl)-phenyl]-piperazine-1-carboxylicacid benzyl ester

A procedure similar to Example 9, step (c) was followed using 153 mg(0.349 mmol) of4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-piperazine-1-carboxylicacid benzyl ester (as prepared in the previous step), 97.7 mg (1.75mmol) of iron powder, 187 mg (3.49 mmol) of ammonium chloride in 10 mLof EtOH-water (2:1) to afford 104 mg (73%) of the corresponding anilineafter chromatography on silica with 4-12% EtOAc-dichloromethane. Theaniline (100 mg) together with 33.6 mg (0.245 mmol) of5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 42.7 μL(0.490 mmol) of oxalyl chloride, and 64.1 μL (0.368 mmol) of DIEAafforded, after chromatography on a 20-g silica SPE column with 2%EtOAc-dichloromethane, 118 mg (91%) of the title compound as a lightyellow solid: ¹H-NMR (CDCl₃; 400 MHz): δ 9.59 (br s, H), 8.31 (d, 1H,J=8.9 Hz), 7.33-7.38 (m, 5H), 7.21, 7.24 (AB q, 2H, J=3.7 Hz), 6.79 (d,1H, J=2.6 Hz), 6.72 (dd, 1H, J=8.9, 2.6 Hz), 5.17 (s, 2H), 3.66-3.69 (m,4H), 3.12 (br s, 4H), 2.97-3.00 (m, 2H), 2.69-2.75 (m, 2H), 1.83-1.86(m, 2H), 1.50-1.65 (m, 1H), 1.46-1.52 (m, 2H) and 1.07 (d, 3H, J=6.2Hz). Mass spectrum (ESI, m/z): Calcd. for C₃₀H₃₃N₅O₄, 528.3 (M+H), found528.1.

Example 154-[4-[(5-Cyano-furan-2-carbonyl)-amino]-3-(4-methyl-piperidin-1-yl)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

a) 1-[3-(4-Methyl-piperidin-1-yl)-4-nitro-phenyl]-piperazine

The procedure of Example 4, step (b) was followed using 460 mg (1.81mmol) of 1-(5-chloro-2-nitro-phenyl)-4-methyl-piperidine (as prepared inthe Example 12, step (a)) and 3.12 g (36.2 mmol) of piperazine for 24 hto afford, after chromatography on a 20-g silica SPE column with 0-10%MeOH-dichloromethane, 518 mg (94%) of the title compound as an orangeresin: Mass spectrum (ESI, m/z): Calcd. for C₁₆H₂₄N₄O₂, 305.2 (M+H),found 305.1.

b)4-[3-(4-Methyl-piperidin-1-yl)-4-nitro-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

A solution of 235 mg (0.772 mmol) of1-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-piperazine (as preparedin the previous step) and 253 mg (1.16 mmol) of di-t-butyl dicarbonatein 8 mL of THF-dichloromethane (1:1) was stirred at RT for 26 h and thenconcentrated in vacuo. Chromatography of the resulting oil on a 10-gsilica SPE column with 50% dichloromethane-hexane followed by 2-5%EtOAc-dichloromethane afforded 300 mg (96%) of the title compound as acrystalline yellow solid: Mass spectrum (ESI, m/z): Calcd. forC₂₁H₃₂N₄O₄, 405.2 (M+H), found 405.1.

c)4-[4-[(5-Cyano-furan-2-carbonyl)-amino]-3-(4-methyl-piperidin-1-yl)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

The procedure of Example 4, step (c) was followed using 145 mg (0.358mmol) of4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (as prepared in the previous step), 70 mg of 10%palladium on carbon (50% by weight water), 49.1 mg (358 mmol) of5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 62.4 μL(0.716 mmol) of oxalyl chloride, and 93.6 μL (0.537 mmol) of DIEA.Chromatography on a 20-g silica SPE column with 20-40%EtOAc-dichloromethane followed by recrystallization from EtOAc-hexaneafforded 156 mg (88%) of the title compound as a light yellow solid:¹H-NMR (CDCl₃; 400 MHz): δ 9.60 (br s, 1H), 8.32 (d, 1H, J=8.9 Hz),7.22, 7.24 (AB q, 2H, J=3.7 Hz), 6.79 (d, 1H, J=2.6 Hz), 6.72 (dd, 1H,J=8.9, 2.6 Hz), 3.58-3.60 (m, 4H), 3.10 (br s, 4H), 2.97-3.00 (m, 2H),2.70-2.75 (m, 2H), 1.82-1.85 (m, 2H), 1.55-1.65 (m, 1H), 1.49 (s, 9H),1.45-1.55 (m, 2H, partially obscured by t-Bu peak) and 1.07 (d, 3H,J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C₂₈H₃₇N₅O₄, 494.3 (M+H),found 494.1.

Example 16 5-Cyano-furan-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-piperazin-1-yl-phenyl]-amidetris(trifluoroacetic acid salt)

To 34.2 mg (0.0693 mmol) of4-[4-[(5-cyano-furan-2-carbonyl)-amino]-3-(4-methyl-piperidin-1-yl)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (as prepared in Example 15, step (c)) was added 4mL of trifluoroacetic acid-dichloromethane-water (10:30:1) and thesolution stirred for 30 min at RT followed by immediate concentration invacuo at 20° C. The resulting glass was crystallized from CHCl₃ at −78°C. followed by concentration from EtOAc-dichloromethane (1:1, 2×2 mL) toafforded 41.7 mg (82%) of the title compound as a cream-colored solid.The ratio of protons in the ¹H-NMR relative and the ratio of fluorinesin the ¹⁹F-NMR of the product relative to the protons and fluorines inan external ¹H/¹⁹F standard indicated the presence of three TFAmolecules per product molecule: Mass spectrum (ESI, m/z): Calcd. forC₂₂H₂₇N₅O₂, 394.2 (M+H), found 394.2.

Example 17 5-Cyano-furan-2-carboxylic acid[4-(4-acetyl-piperazin-1-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide

To 40.0 mg (0.0546 mmol) of 5-cyano-furan-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-piperazin-1-yl-phenyl]-amidetris(trifluoroacetic acid salt) (as prepared in Example 16) suspended in2 mL of anh THF was added 6.2 μL (0.0655 mmol) of acetic anhydridefollowed by 47.6 μL (0.716 mmol) of DIEA. After stirring for 20 min atRT, the mixture was poured into satd aq NaHCO₃ (20 mL) and extractedwith EtOAc (20 mL). The extract was dried (Na₂SO₄) and concentrated invacuo and the resulting solid was chromatographed on a 2-g silica SPEcolumn with 25-40% EtOAc-dichloromethane to afford 22.0 mg (92%) of thetitle compound as a crystalline yellow solid: ¹H-NMR (CDCl₃; 400 MHz): δ9.59 (br s, 1H), 8.32 (d, 1H, J=8.9 Hz), 7.22, 7.25 (AB q, 2H, J=3.7 Hz,partially obscured by CHCl₃ peak), 6.79 (d, 1H, J=2.6 Hz), 6.72 (dd, 1H,J=8.9, 2.6 Hz), 3.77-3.80 (m, 2H), 3.62-3.64 (m, 2H), 3.11-3.17 (m, 4H),2.98-3.01 (m, 2H), 2.73-2.76 (m, 2H), 2.15 (s, 3H), 1.83-1.86 (m, 2H),1.52-1.62 (m, 1H), 1.46-1.56 (m, 2H) and 1.07 (d, 3H, J=6.2 Hz). Massspectrum (ESI, m/z): Calcd. for C₂₄H₂₉N₅O₃, 436.2 (M+H), found 436.2.

Example 18 5-Cyano-furan-2-carboxylic acid[4-(4-methanesulfonyl-piperazin-1-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide

The procedure of Example 17 was followed using 40.0 mg (0.0546 mmol) of5-cyano-furan-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-piperazin-1-yl-phenyl]-amidetris(trifluoroacetic acid salt) (as prepared in Example 16), 7.6 μL(0.0655 mmol) of is methanesulfonyl chloride and 47.6 μL (0.716 mmol) ofDIEA. Chromatography on a 2-g silica SPE column with 5-10%EtOAc-dichloromethane followed by concentration from EtOAc-hexane (1:1,2 mL) afforded 23.3 mg (91%) of the title compound as a crystallineyellow solid: ¹H-NMR (CDCl₃; 400 MHz): δ 9.59 (br s, 1H), 8.33 (d, 1H,J=8.8 Hz), 7.22, 7.25 (AB q, 2H, J=3.7 Hz, partially obscured by CHCl₃peak), 6.79 (d, 1H, J=2.7 Hz), 6.73 (dd, 1H, J=8.8, 2.7 Hz), 3.39-3.41(m, 4H), 3.25-3.27 (m, 4H), 2.98-3.01 (m, 2H), 2.84 (s, 3H), 2.70-2.76(m, 2H), 1.83-1.87 (m, 2H), 1.50-1.65 (m, 1H), 1.42-1.58 (m, 2H) and1.08 (d, 3H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. forC₂₃H₂₉N₅O₄S, 472.2 (M+H), found 472.2.

Example 19

Carbonic acid tert-butyl ester2-{4-[4-[(5-cyano-furan-2-carbonyl)-amino]-3-(4-methyl-piperidin-1-yl)-phenyl]-piperazin-1-yl}-ethylester

a)2-{4-[3-(4-Methyl-piperidin-1-yl)-4-nitro-phenyl]-piperazin-1-yl}-ethanol

The procedure of Example 4, step (b) was followed using 810 mg (3.18mmol) of 1-(5-chloro-2-nitro-phenyl)-4-methyl-piperidine (as prepared inthe Example 12, step (a)) and 1.95 mL (15.9 mmol) of1-(2-hydroxyethyl)piperazine for 14 h to afford 1.11 g (100%) of thetitle compound as a yellow solid: Mass spectrum (ESI, m/z): Calcd. forC₁₈H₂₈N₄O₃, 349.2 (M+H), found 349.2.

b) Carbonic acid tert-butyl ester2-{4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-piperazin-1-yl}-ethylester

A solution of 320 mg (0.919 mmol) of2-{4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-piperazin-1-yl}-ethanol(as prepared in the previous step), 240 mg (1.10 mmol) of di-t-butyldicarbonate and 9.0 mg (0.074 mmol) of 4-(dimethylamino)pyridine in 8 mLof THF was stirred at 50° C. for 0.5 h and then concentrated in vacuo.Chromatography of the resulting oil on a 20-g silica SPE column with0-10% EtOAc-dichloromethane afforded 342 mg (83%) of the title compoundas a yellow resin: Mass spectrum (ESI, m/z): Calcd. for C₂₃H₃₆N₄O₅,449.3 (M+H), found 449.1.

c) Carbonic acid tert-butyl ester2-{4-[4-[(5-cyano-furan-2-carbonyl)-amino]-3-(4-methyl-piperidin-1-yl)-phenyl]-piperazin-1-yl}-ethylester

The procedure of Example 4, step (c) was followed using 156 mg (0.348mmol) of carbonic acid tert-butyl ester2-{4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-piperazin-1-yl}-ethylester (as prepared in the previous step), 78 mg of 10% palladium oncarbon (50% by weight water), 52.5 mg (383 mmol) of5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 50.1 μL(0.575 mmol) of oxalyl chloride, and 121 μL (0.696 mmol) of DIEA.Chromatography on a 10-g silica SPE column with 5-20%EtOAc-dichloromethane afforded 176 mg (94%) of the title compound as alight yellow solid: ¹H-NMR (CDCl₃; 400 MHz): δ 9.60 (br s, 1H), 8.29 (d,1H, J=8.9 Hz), 7.21, 7.24 (AB q, 2H, J=3.7 Hz), 6.79 (d, 1H, J=2.6 Hz),6.71 (dd, 1H, J=8.9, 2.6 Hz), 4.23 (t, 2H, J=5.8 Hz), 3.16-3.19 (m, 4H),2.97-3.00 (m, 2H), 2.67-2.75 (m, 8H), 1.82-1.84 (m, 4H), 1.50-1.65 (m,1H), 1.46-1.58 (m, 2H, partially obscured by t-Bu peak), 1.49 (s, 9H),and 1.07 (d, 3H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. forC₂₉H₃₉N₅O₅, 538.3 (M+H) and 438.2 (M-BOC+2H), found 538.2, 438.2.

Example 20 5-Cyano-furan-2-carboxylic acid[4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-2-(4-methyl-piperidin-1-yl)-phenyl]-amidetrifluoroacetic acid salt

To 92.2 mg (0.172 mmol) of carbonic acid tert-butyl ester2-{4-[4-[(5-cyano-furan-2-carbonyl)-amino]-3-(4-methyl-piperidin-1-yl)-phenyl]-piperazin-1-yl}-ethylester (as prepared in Example 19, step (c)) was added 2 mL oftrifluoroacetic acid-dichloromethane-water (20:5:1) and the solutionstirred for 2 h at RT followed by concentration in vacuo. The resultingresin was crystallized from hot CHCl₃ to afford 154 mg pale yellowcrystals. This material in 8 mL of EtOAc was treated with 3 g K₂CO₃ andwater (2 mL) and stirred for 30 min. Anh Na₂SO₄ was added, the mixturefiltered and the filtrate dried over anh K₂CO₃ and concentrated in vacuoto afford the title compound as a yellow solid. The ratio of protons inthe ¹H-NMR relative and the ratio of fluorines in the ¹⁹F-NMR of theproduct relative to the protons and fluorines in an external ¹H/¹⁹Fstandard indicated the presence of 1.4 TFA molecules per productmolecule: ¹H-NMR (DMSO-d₆; 400 MHz): δ 9.58 (br s, 1H), 8.91 (d, 1H,J=8.9 Hz), 7.79 (d, 1H, J=3.8 Hz), 7.44 (d, 1H, J=3.8 Hz), 6.80 (d, 1H,J=2.6 Hz), 6.69 (dd, 1H, J=8.9, 2.6 Hz), 4.47 (t, 1H, J=5.3 Hz),3.51-3.55 (m, 2H), 3.09-3.12 (m, 4H), 2.92-2.95 (m, 2H), 2.68-2.74 (m,2H), 2.53-2.55 (m, 4H), 2.43 (t, 2H, J=6.2 Hz), 1.75-1.77 (m, 2H),1.48-1.54 (m, 1H), 1.31-1.41 (m, 2H), and 0.99 (d, 3H, J=6.4 Hz). Massspectrum (ESI, m/z): Calcd. for C₂₄H₃₁N₅O₃, 438.2 (M+H), found 438.2.

Example 21 5-Cyano-furan-2-carboxylic acid[5-fluoro-4-(4-methyl-piperazin-1-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide

a) 1-(5-Chloro-4-fluoro-2-nitro-phenyl)-4-methyl-piperidine and1-(5-chloro-2-fluoro-4-nitro-phenyl)-4-methyl-piperidine

The procedure of Example 4, step (a) was followed using 575 mg (2.74mmol) of 2,4-dichloro-5-fluoronitrobenzene (Oakwood) and 280 μL (2.39mmol) of 1-methylpiperidine in 4 μL of EtOH except the reaction wasstirred at 78° C. for 16 h to give 670 mg of a ca. 1:1:1 mixture by¹H-NMR of 2,4-dichloro-5-fluoronitrobenzene and the two title compounds.Chromatography on a silica gel with 20-40% dichloromethane-hexaneafforded pure analytical samples of each product which werecharacterized by 2-dimensional ¹³C—¹H correlation NMR spectra to assigncarbons and then by fluorine-carbon couplings to determine the higherR_(f) product to be1-(5-chloro-4-fluoro-2-nitro-phenyl)-4-methyl-piperidine: Mass spectrum(ESI, m/z): Calcd. for C₁₂H₁₄ClFN₂O₂, 273.1 (M+H), found 273.0, and thelower R_(f) product to be1-(5-chloro-2-fluoro-4-nitro-phenyl)-4-methyl-piperidine: Mass spectrum(ESI, m/z): Calcd. for C₁₁H₁₂Cl₂N₂O₂, 275.0 (M+H), found 273.1.Fractions containing the higher R_(f) product (60% purity by ¹H-NMR)were carried on to the following reaction without further purification.

b)1-[2-Fluoro-5-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-4-methyl-piperazine

The procedure of Example 4, step (b) was followed using 88 mg (0.19 mmolbased on 60% purity by ¹H-NMR) of1-(5-chloro-4-fluoro-2-nitro-phenyl)-4-methyl-piperidine (as prepared inthe previous step) and 105 μL (0.950 mmol) of 1-methylpiperazine at 150°C. for 16 h. Chromatography on a 10-g silica SPE column with 24%MeOH-dichloromethane afforded 60 mg (94%) of the title compound as acrystalline orange solid: Mass spectrum (ESI, m/z): Calcd. forC₁₇H₂₅FN₄O₂, 337.2 (M+H), found 337.2.

c) 5-Cyano-furan-2-carboxylic acid[5-fluoro-4-(4-methyl-piperazin-1-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide

The procedure of Example 4, step (c) was followed using 58.5 mg (0.174mmol) of1-[2-fluoro-5-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-4-methyl-piperazine(as prepared in the previous step), 29 mg of 10% palladium on carbon(50% by weight water), 28.6 mg (0.209 mmol) of 5-cyanofuran-2-carboxylicacid (as prepared in Example 1), 27.3 μL (0.314 mmol) of oxalylchloride, and 72.8 μL (0.418 mmol) of DIEA except the isolated impureproduct was dissolved in 10 mL of EtOAc, washed with 1M K₂CO₃ (2×5 mL),dried (Na₂SO₄) and then concentrated in vacuo. Chromatography on a 5-gsilica SPE column with 1-3% MeOH-dichloromethane afforded 60.8 mg (82%)of the title compound as a crystalline yellow solid: ¹H-NMR (CDCl₃; 400MHz): δ 9.76 (br s, 1H), 8.19 (d, 1H, J=14.1 Hz), 7.22, 7.26 (AB q, 2H,J=3.7 Hz), 6.80 (d, 1H, J=8.5 Hz), 3.11-3.19 (m, 4H), 2.92-2.95 (m, 2H),2.69-2.76 (m, 2H), 2.55-2.65 (br m, 4H), 2.37 (s, 3H), 1.82-1.86 (m,2H), 1.5-1.7 (br m, 1H) and 1.42-1.53 (m, 2H). Mass spectrum (ESI, m/z):Calcd. for C₂₃H₂₈FN₅O₂, 426.2 (M+H), found 426.3.

Example 22 5-Cyano-furan-2-carboxylic acid(4-azido-2-piperidin-1-yl-phenyl)-amide

a) 1-(5-Fluoro-2-nitro-phenyl)-piperidine

To a solution of 2,4-difluoronitrobenzene (2.09 g, 13.1 mmol) in EtOH(10 mL) at ambient temperature was added piperidine (3.35 g, 39.4 mmol)dropwise. The reaction was allowed to stir overnight and concentrated invacuo. The residue was dissolved in EtOAc (100 mL), washed with water(2×100 mL), dried (Na₂SO₄) and concentrated in vacuo. Purification bysilica gel column chromatography afforded 1.10 (37%) of the titlecompound as an oil. Mass spectrum (ESI, m/z): Calcd. for C₁₁H₁₃FN₂O₂,225.1 (M+H), found 225.1.

b) 1-(5-Azido-2-nitro-phenyl)-piperidine

To a solution of 1-(fluoro-2-nitro-phenyl)-piperidine (389 mg, 1.73mmol, as prepared in the previous step) in 5, mL of DMF was added sodiumazide (169 mg, 2.60 mmol) and the resultant mixture heated to 50° C. for14 h, and then 80° C. for 6 h. The reaction was diluted with EtOAc (100mL), washed with water (2×50 mL), dried (Na₂SO₄) and concentrated invacuo. Purification by preparative TLC (50% EtOAc-hexane) afforded 316mg (74%) of the title compound as a tan solid. Mass spectrum (ESI, m/z):Calcd. for C₁₁H₁₃N₅O₂, 248.1 (M+H), found 247.9.

c) 5-Cyano-furan-2-carboxylic acid(4-azido-2-piperidin-1-yl-phenyl)-amide

To a solution of sodium hydrosulfite (936 mg, 5.30 mmol) in 8 mL ofwater was added 1-(5-azido-2-nitro-phenyl)-piperidine (133 mg, 0.530mmol, as prepared in the previous step) in 4 mL of THF dropwise. After25 min the reaction was poured into 50 mL of brine, extracted with EtOAc(3×30 mL), dried (Na₂SO₄), and concentrated in vacuo. The crude productwas then allowed to react in a manner similar to Example 4, step (c),with 5-cyano-furan-2-carbonyl chloride (31 mg, 0.20 mmol) in thepresence of DIEA (203 μL, 1.16 mmol) to afford 8 mg (12%) of the titlecompound as an amber solid. ¹H-NMR (CDCl₃; 400 MHz): δ 9.58 (s, 1H),8.44 (d, 1H, J=7.8 Hz), 7.22-7.30 (m, 2H), 6.81-6.89 (m, 2H), 2.81-2.86(m, 4H), 1.79-1.82 (m, 4H), 1.62-1.65 (m, 2H); Mass spectrum (ESI, m/z):Calcd. for C₁₇H₁₆N₆O₂, 337.1 (M+H), found 337.0.

Example 23 5-(N-Hydroxycarbamimidoyl)-furan-2-carboxylic acid(2,4-di-piperidin-1-yl-phenyl)-amide

a) 5-Cyano-furan-2-carboxylic acid (2,4-di-piperidin-1-yl-phenyl)-amide

To a solution of 2,4-difluoronitrobenzene (2.09 g, 13.1 mmol) in EtOH(10 mL) at ambient temperature was added piperidine (3.35 g, 39.4 mmol)dropwise. The reaction was allowed to stir overnight and concentrated invacuo. The residue was dissolved in EtOAc (100 mL), washed with water(2×100 mL), dried (Na₂SO₄) and concentrated in vacuo. Purification bysilica gel column chromatography (10% EtOAc-hexane) afforded 610 mg(16%) of 2,4-dipiperidinylnitrobenzene as an oil.2,4-dipiperidinylnitrobenzene (273 mg, 0.94 mmol) was then stirred inthe presence of 168 mg of 5% Pd—C in 10 mL of MeOH under H₂ for 2 h. Thereaction was filtered through Celite and concentrated in vacuo to afford230 mg of 2,4-dipiperidinylaminobenzene (94%) as an oil. Using aprocedure similar to Example 4, step (c), 2,4-dipiperidinylaminobenzene(100 mg, 0.38 mmol) was allowed to react with 5-cyano-furan-2-carbonylchloride (73 mg, 0.46 mmol) in the presence of DIEA (145 μL, 0.83 mmol)to afford 90 mg 62%) of the title compound as a yellow solid. Massspectrum (ESI, m/z): Calcd. for C₂₂H₂₆N₄O₂, 379.2 (M+H), found 379.2.

b) 5-(N-Hydroxycarbamimidoyl)-furan-2-carboxylic acid(2,4-di-piperidin-1-yl-phenyl)-amide

To a solution of 5-cyano-furan-2-carboxylic acid(2,4-di-piperidin-1-yl-phenyl)-amide (48 mg, 0.12 mmol, as prepared inthe previous step) in 1 mL of EtOH at room temperature was added NH₂OH(26 mg, 0.4 mmol, 50% wt/H₂O) via syringe. The reaction was heated toreflux for 10 min, and then cooled to 0° C. The bright yellowprecipitate was filtered, washed with cold 50% EtOH—H₂O (2 mL) and driedto afford 11 mg (23%) of the title compound as a bright yellow solid.¹H-NMR (DMSO-d₆; 400 MHz): δ 9.83 (s, 1H), 9.37 (s, 1H), 7.84 (d, 1H,J=9.0 Hz), 7.21 (d, 1H, J=3.5 Hz), 6.89 (d, 1H, J=3.6 Hz), 6.74 (s, 1H),6.66 (d, 1H, J=8.8 Hz), 5.96 (br s, 2H), 3.08-3.10 (m, 4H), 2.78-2.77(m, 4H), 1.71-1.52 (m, 12H); Mass spectrum (ESI, m/z): Calcd. forC₂₂H₂₉N₅O₃ 412.2 (M+H), found 412.2;

Example 24 5-Cyano-furan-2-carboxylic acid[4-(4-methyl-pyrazol-1-yl)-2-piperidin-1-yl-phenyl]-amide

a) 1-[5-(4-Methyl-pyrazol-1-yl)-2-nitro-phenyl]-piperidine

A solution of 1-(5-fluoro-2-nitro-phenyl)-piperidine (98 mg, 0.43 mmol,as prepared in Example 22, step (a), 3-methylpyrazole (49.2 mg, 0.6mmol), and NaOH (22.4 mg, 0.56 mmol) were heated in 3 mL of DMSO at 90°C. overnight. The reaction was diluted with EtOAc (50 mL), washed withwater (2×50 mL), dried (Na₂SO₄) and concentrated in vacuo to afford 117mg (95%) the title compound as a yellow solid. Mass spectrum (ESI, m/z):Calcd. for C₁₅H₁₈N₄O₂ 287.1 (M+H), found 287.1.

b) 5-Cyano-furan-2-carboxylic acid[4-(4-methyl-pyrazol-1-yl)-2-piperidin-1-yl-phenyl]-amide

1-[5-(4-Methyl-pyrazol-1-yl)-2-nitro-phenyl]-piperidine (110 mg, 0.38mmol, as prepared in the previous step) was allowed to react with TiCl₃(2.3 mL, 3.8 mmol) in 3 mL of THF. The reaction was quenched with satdaq NaHCO₃ (15 mL) and poured into 25 mL of EtOAc. The organic layer wasseparated, washed with water (2×25 mL), dried (Na₂SO₄), and concentratedin vacuo to afford 94 mg (95%) of4-(4-methyl-pyrazol-1-yl)-2-piperidin-1-yl-phenylamine, which wasallowed to react in a similar manner to Example 4, step (c), with5-cyano-furan-2-carbonyl chloride (84 mg, 0.54 mmol) in the presence ofDIEA (137 μL, 0.79 mmol) to afford 52.7 mg (47%) of the title compoundas a light yellow solid. ¹H-NMR (CDCl₃; 400 MHz): δ 9.65 (s, 1H), 8.50(d, 1H, J=8.8 Hz), 7.92 (s, 1H), 7.71 (s, 1H), 7.37 (dd, 1H, J=2.5, 8.8Hz), 7.29 (d, 1H, J=3.8 Hz), 7.23 (d, 1H, J=3.7 Hz), 6.46-6.45 (m, 1H),2.94-2.89 (m, 4H), 2.14 (s, 3H), 1.85-1.80 (m, 4H), 1.66 (br s, 2H);Mass spectrum (ESI, m/z): Calcd. for C₂₁H₂₁N₅O₂, 376.1 (M+H), found376.1.

Example 25 4-Methyl-piperazine-1-carboxylic acid{4-[(5-cyano-furan-2-carbonyl)-amino]-3-piperidin-1-yl-phenyl}-methyl-amide

a) Methyl-(4-nitro-3-piperidin-1-yl-phenyl)-amine

A solution of 1-(5-fluoro-2-nitro-phenyl)-piperidine (200 mg, 0.890mmol) in 4 mL of 2M methylamine in MeOH was heated in a sealed tube for12 h at 80° C. Removal of the solvent under vacuum affordedmethyl-(4-nitro-3-piperidin-1-yl-phenyl)-amine (209 mg, 100%). Massspectrum (ESI, m/z): Calcd. for C₁₂H₁₇N₃O₂, 236.1 (M+H), found 236.1.

b) 4-Methyl-piperazine-1-carboxylic acidmethyl-(4-nitro-3-piperidin-1-yl-phenyl)-amide

To a solution of triphosgene (40.6 mg, 0.13 mmol) in 2 mL of CH2Cl2 wasadded methyl-(4-nitro-3-piperidin-1-yl-phenyl)-amine (88 mg, 0.37 mmol)and DIEA (38 μL, 0.22 mmol) in 2 mL of CH₂Cl₂ over a 15 min. period. Asolution of N-methylpiperazine (1.2 eq, 41 μL) and DIEA (38 μL, 0.22mmol) in 1.5 mL of CH₂Cl₂ were then added via cannula and stirring wascontinued for 10 min. The reaction was diluted with CHCl₃ (50 mL) andwashed with satd aq NaHCO₃ (50 mL). The organic layer was dried (Na₂SO₄)and concentrated in vacuo to give 115 mg (86%) of the title compound ayellow oil. Mass spectrum (ESI, m/z): Calcd. for C₁₈H₂₇N₅O₃, 362.2(M+H), found 362.2.

c) 4-Methyl-piperazine-1-carboxylic acid{4-[(5-cyano-furan-2-carbonyl)-amino]-3-piperidin-1-yl-phenyl}-methyl-amide

Using a procedure similar to Example 23, step (a),4-methyl-piperazine-1-carboxylic acidmethyl-(4-nitro-3-piperidin-1-yl-phenyl)-amide (110 mg, 0.3 mmol, asprepared in the previous step) was stirred in MeOH in the presence of 5%Pd—C (65 mg) to afford crude 4-methyl-piperazine-1-carboxylic acid(4-amino-3-piperidin-1-yl-phenyl)-methyl-amide as an oil, which in amanner similar to Example 4, step (c) was coupled to5-cyano-furan-2-carbonyl chloride (64.6 μL, 412 mmol) in the presence ofDIEA (115 μL, 0.6 mmol) using a procedure similar to Example 2 to afford54.4 mg (40%) of the title compound as a bright yellow solid. ¹H-NMR(CDCl₃, 400 MHz): δ 9.62 (s, 1H), 8.41 (d, 1H, J=8.5 Hz), 7.29 (d, 1H,J=3.8 Hz), 7.24 (d, 1H, J=3.8 Hz), 6.95-6.92 (m, 2H), 3.24-3.26 (M, 4H),3.22 (s, 3H), 2.84-2.82 (m, 4H), 2.21-2.26 (m, 7H), 1.84-1.79 (m, 4H),1.66 (m, 2H); Mass spectrum (ESI, m/z): Calcd. for C₂4H₃₀N₆O₃, 451.2(M+H), found 451.1.

Example 26 5-Cyano-furan-2-carboxylic acid[4-(methanesulfonyl-methyl-amino)-2-piperidin-1-yl-phenyl]-amide

a) N-Methyl-(4-nitro-3-piperidin-1-yl-phenyl)-amine

A solution of 1-(5-fluoro-2-nitro-phenyl)-piperidine (200 mg, 0.89 mmol)in 4 mL of 2M methylamine in MeOH was heated in a sealed tube for 12 hat 80° C. Removal of the solvent under vacuum affordedmethyl-(4-nitro-3-piperidin-1-yl-phenyl)-amine (209 mg, 100%). Massspectrum (ESI, m/z): Calcd for C₁₂H₁₇N₃O₂, 236.1 (M+H), found 236.1.

b) N-Methyl-N-(4-nitro-3-piperidin-1-yl-phenyl)-methanesulfonamide

To a solution of N-methyl-(4-nitro-3-piperidin-1-yl-phenyl)-amine (128mg, 0.54 mmol, as prepared in the previous step) and triethylamine (301μL, 2.16 mmol) in 4 mL of CH₂Cl₂ was added mesyl chloride (125 μL, 1.62mmol) via microsyringe and the reaction was allowed to stir overnight.At this time it was diluted with CHCl₃ (50 mL), washed with satd aqNaHCO₃ (2×50 mL), and dried (Na₂SO₄). Concentration of the solvent invacuo and purification of the crude material using preparative TLC (4%MeOH—CHCl₃) afforded 154 mg (91%) of the title compound as an oil. Massspectrum (ESI, m/z): Calcd. for C₁₃H₁₉N₃O₄S, 314.1 (M+H), found 314.1.

c) 5-Cyano-furan-2-carboxylic acid[4-(methanesulfonyl-methyl-amino)-2-piperidin-1-yl-phenyl]-amide

Using a procedure similar to Example 23, step (a),N-methyl-N-(4-nitro-3-piperidin-1-yl-phenyl)-methanesulfonamide (89 mg,0.28 mmol) was stirred with 5% Pd—C (55 mg) under H₂ to afford 72 mg(91%) of N-(4-Amino-3-piperidin-1-yl-phenyl)-N-methyl-methanesulfonamideas an oil. Using a procedure similar to Example 4, step (c),N-(4-amino-3-piperidin-1-yl-phenyl)-N-methyl-methanesulfonamide wascoupled to 5-cyano-furan-2-carbonyl chloride (77 mg, 0.49 mmol) in thepresence of DIEA (107 μL, 0.55 mmol) to afford 26.2 mg (23%) of thetitle compound as a yellow powder. ¹H-NMR (DMSO-d₆, 400 MHz): δ 9.66 (s,1H), 8.10 (d, 1H, J=8.7 Hz), 7.81 (d, 1H, J=3.8 Hz), 7.52 (d, 1H, J=3.7Hz),), 7.26 (d, 1H, J=2.8 Hz), 7.21-7.19 (m, 1H), 3.23 (s, 3H), 2.95 (s,3H), 2.84-2.82 (m, 4H), 1.72 (br s, 4H), 1.57 (br s, 2H); Mass spectrum(ESI, m/z): Calcd. for C₁₉H₂₂N₄O₄S, 403.1 (M+H), found 403.1.

Example 27 Acetic acid{4-[(5-cyano-furan-2-carbonyl)-amino]-3-piperidin-1-yl-phenylcarbamoyl}-methylester

a) 4-Nitro-3-piperidin-1-yl-phenylamine

A solution of 1-(5-fluoro-2-nitro-phenyl)-piperidine (514 mg, 2.29 mmol)in 10 mL of saturated NH₃-MeOH were heated in a sealed tube at 110° C.for 48 h. The result was concentrated in vacuo and purified bypreparative thin layer chromatography to afford 240 mg (47%) of thetitle compound. Mass spectrum (ESI, m/z): Calcd. for C₁₁H₁₅N₃O₂, 222.1(M+H), found 222.2.

b) Acetic acid (4-amino-3-piperidin-1-yl-phenylcarbamoyl)-methyl ester

To a solution of 4-nitro-3-piperidin-1-yl-phenylamine (78 mg, 0.35 mmol)and DIEA (152 mL, 0.8 mmol) in 4 mL of CH₂Cl₂ was addedacetoxyacetychloride (57 mL, 0.50 mmol) via microsyringe. After 1 h, thereaction was diluted with CH₂Cl₂ (50 mL), washed with satd aq NaHCO₃ (50mL) and dried. The solvent was filtered through SiO₂ and concentrated invacuo to afford 106 mg (99%) of the title compound as an oil. Using aprocedure similar to Example 1, the crude product was stirred with 5%Pd—C (50 mg) under H₂ to afford 80 mg (78%) of the title compound as anoil. Mass spectrum (ESI, m/z): Calcd. for C₁₅H₂₁N₃O₃, 292.1 (M+H), found292.1.

c) Acetic acid{4-[(5-cyano-furan-2-carbonyl)-amino]-3-piperidin-1-yl-phenylcarbamoyl}-methylester

Using a procedure similar to Example 4, step (c), acetic acid(4-amino-3-piperidin-1-yl-phenylcarbamoyl)-methyl ester (80 mg, 0.27mmol) was allowed to react with 5-cyano-furan-2-carbonyl chloride (42mg, 0.27 mmol) in the presence of DIEA (0.10 mL, 0.59 mmol) to afford 22mg (20%) of the title compound as a yellow solid. ¹H-NMR (CDCl₃; 400MHz): δ 9.66 (s, 1H), 8.40 (d, 1H, J=9.0 Hz), 7.73-7.76 (m, 2H),7.27-7.28 (m, 1H), 7.22 (d, 1H, J=2.7 Hz), 7.08 (dd, 1H, J=2.3, 8.7 Hz),4.68 (s, 2H), 2.84-2.86 (m, 4H), 2.24 (s, 3H), 1.82-1.84 (m, 4H), 1.68(br s, 2H); Mass spectrum (ESI, m/z): Calcd. for C₂₁H₂₂N₄O₅, 411.1(M+H), found 411.1.

Example 28 5-Cyano-furan-2-carboxylic acid(4-methanesulfonylamino-2-piperidin-1-yl-phenyl)-amide

a) N-(4-Nitro-3-piperidin-1-yl-phenyl)-bis-methanesulfonamide

To a solution of 4-nitro-3-piperidin-1-yl-phenylamine (75 mg, 0.54 mmol,as prepared in Example 27, step (a)) and N-methymorpholine (0.67 mmol,74 μL) in 4 mL of CH₂Cl₂ was added mesyl chloride (33 μL, 0.42 mmol) viamicrosyringe and the reaction was allowed to stir overnight. At thistime it was diluted with CHCl₃ (50 μL), washed with satd aq NaHCO₃ (2×50mL), and dried (Na₂SO₄). Concentration of the solvent in vacuo andpurification of the crude material using preparative TLC (4% MeOH—CHCl₃)afforded 21 mg (21%) of the mono sulfonamide and 40 mg (32%) of thetitle compound as a yellow oil. Mass spectrum (ESI, m/z): Calcd. forC₁₃H₁₉N₃O₆S₂, 378.0 (M+H), found 300.0 [M—SO₂Me]+2H.

b) 5-Cyano-furan-2-carboxylicacid-(4-methanesulfonylamino-2-piperidin-1-yl-phenyl)-amide

Using a procedure similar to Example 23, step (a),N-(4-nitro-3-piperidin-1-yl-phenyl)-bis-methanesulfonamide (40 mg, 0.1mmol, as prepared in the previous step) was stirred with 20 mg 5% Pd—Cin 5 mL MeOH under H₂ to afford 35 mg (100%) of the title compound as anoil, which was used immediately without further purification. Using aprocedure similar to Example 4, step (c),N-(4-amino-3-piperidin-1-yl-phenyl)-bis-methanesulfonamide (35 mg, 0.10mmol)) was allowed to react with 5-cyano-furan-2-carbonyl chloride (17mg, 0.11 mmol) in the presence of DIEA (38 μL, 0.22 mmol) to afford 9.7mg (25%) of the title compound as a yellow solid. ¹H-NMR (CDCl₃; 400MHz): δ 9.59 (s, 1H), 8.43 (d, 1H, J=8.7 Hz), 7.31 (d, 1H, J=3.7 Hz),7.25 (dd, 1H, J=0.7, 3.7 Hz),), 7.18 (d, 1H, J=2.2 Hz), 6.94-6.98 (m,1H), 6.47 (s, 1H), 3.02 (s, 3H), 2.86-2.88 (m, 4H), 1.82-1.85 (m, 4H),1.61 (br s, 2H); Mass spectrum (ESI, m/z): Calcd. for C₁₈H₂₀N₄O₄S, 389.1(M+H), found 389.1.

Example 29 5-Cyano-furan-2-carboxylic acid[4-methyl-6′-(4-methyl-piperidin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]-bipyrazinyl-5′-yl]-amide

a) 6′-Chloro-4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl

To a solution of 2,6-dichloropyrazine (400 mg, 2.68 mmol) in 6 mL ofCH₂Cl₂ was added 4-methylpiperidine (1.2 eq, 3.2 mmol) and allowed tostir overnight. The reaction was diluted with CH₂Cl₂ (50 mL) washed withH₂O (2×50 mL) and dried (K₂CO₃) to give 450 mg (80%) of the titlecompound as a white solid. Mass spectrum (ESI, m/z): Calcd. forC₁₁H₁₅ClN₂, 211.0 (M+H), found 211.1.

b) 6′-Chloro-4-methyl-5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl

To a solution of6′-chloro-4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (450 mg (2.12mmol, as prepared in the previous step) in 7 mL of CH₃CN was addedNO₂BF₄ (198 mg, 1.48 mmol) in three portions. After 10 min, the reactionwas cooled to the freezing point of −50° C. and another 98 mg (0.73mmol) of NO₂BF₄ was added in one portion. The reaction was stirred for20 min, warmed to 0° C., and placed in a freezer overnight. At this timethe reaction was quenched with satd aq NaHCO₃ (50 mL), extracted withEtOAc (2×20 mL), and dried (K₂CO₃). The EtOAc was removed in vacuo andthe crude material was purified by preparative thin layer chromatography(20% EtOAc-hexane) to afford 42 mg (8%) of the title compound as ayellow solid. ¹H-NMR (CDCl₃; 400 MHz): δ 7.65 (s, 1H), 3.91-3.86 (m,2H), 3.11-3.04 (m, 2H), 1.66-1.80 (m, 3H), 1.34-1.24 (m, 2H), 1.01 (d,3H, J=6.4 Hz);

c)4-Methyl-6′-(4-methyl-piperidin-1-yl)-5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl

To 6′-chloro-4-methyl-5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl(32 mg, 0.12 mmol) was added N-methylpiperazine (370 mg, 3.7 mmol) andthe resultant solution was stirred for 15 min. The reaction was dilutedwith EtOAc (50 mL), washed with H₂O (2×20 mL), dried (K₂CO₃) andconcentrated in vacuo to afford 37 mg (96%) of the title compound. Massspectrum (ESI, m/z): Calcd. for C₁₅H₂₄N₆O₂, 321.2 (M+H), found 321.1.

d) 5-Cyano-furan-2-carboxylic acid[4-methyl-6′-(4-methyl-piperidin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]-bipyrazinyl-5′-yl]-amide

Using a procedure similar to Example 23, step (a)4-methyl-6′-(4-methyl-piperidin-1-yl)-5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl(37 mg, 0.11 mmol) was stirred with 20 mg 5% Pd—C in 5 mL MeOH under H₂to afford 32 mg (100%) of the title compound as an oil, which was usedimmediately without further purification. Using a procedure similar toExample 4, step (c),4-methyl-6′-(4-methyl-piperidin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylamine(32 mg, 0.10 mmol)) was allowed to react with 5-cyano-furan-2-carbonylchloride (44.6 mg, 0.28 mmol) in the presence of DIEA (107 μL, 0.610mmol) to afford 10 mg (25%) of the title compound as a dark semi-solid.¹H-NMR (CDCl₃; 400 MHz): δ 8.29 (s, 1H), 7.57 (s, 1H), 7.32 (d, 1H,J=3.6 Hz), 7.24-7.23 (d, 1H, J=3.6 Hz), 3.60-3.57 (m, 6H), 2.87-2.81 (m,2H), 2.57-2.54 (m, 4H), 2.39 (s, 3H), 1.77-1.73 (m, 2H), 1.66-1.55 (m,1H), 1.40-1.32 (m, 2H), 1.02 (d, 3H, J=6.5 Hz); Mass spectrum (ESI,m/z): Calcd. for C₂₁H₂₇N₇O₂, 410.2 (M+H), found 410.2.

Example 30 5-Cyano-furan-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amidehydrochloride

a) 4-(4-Methyl-piperazin-1-yl)-2-piperidin-1-yl-phenylamine

1-(5-Fluoro-2-nitro-phenyl)-piperidine (100 mg, 0.44 mmol) was treatedwith N-methylpiperizine (3 mL) and heated to 80° C. overnight. Thereaction was diluted with EtOAc (10 mL), washed with water (2×10 mL),dried (Na₂SO₄) and concentrated in vacuo to afford 118 mg (88%) of1-methyl-4-(4-nitro-3-piperidin-1-yl-phenyl)-piperazine as an oil. The1-methyl-4-(4-nitro-3-piperidin-1-yl-phenyl)-piperazine (22 mg, 0.07mmol) was stirred with 13 mg 5% Pd—C in 1 mL of MeOH under H₂ for 2 h.The mixture was filtered through SiO₂, eluting with 10% MeOH—CHCl₃, andthe solvent was concentrated in vacuo to give 17 mg (86%) of the titlecompound as a white solid. Mass spectrum (ESI, m/z): Calcd. forC₁₆H₂₆N₄, 275.22 (M+H), found 275.2.

b) 5-Cyano-furan-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amidehydrochloride

Using a procedure similar to Example 4, step (c),4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenylamine (2.84 g, 9.80mmol) was allowed to react with 5-cyano-furan-2-carbonyl chloride (2.42g, 15.6 mmol) in the presence of DIEA (4.26 mL, 24.0 mmol) to afford2.02 g of free base as a yellow solid. The free base was sonicated in 20mL of ether for 5 min, and then cooled to 0° C. At this time 12.8 mL ofa 0.4 M HCL-ether solution was slowly added via syringe, stirring wascontinued for 10 min and the mixture was warmed to room temperature.Another 20 mL of ether was added, the mixture was stirred vigorously,and the solvent removed by a syringe. The resultant powder was driedunder vacuum to afford 2.20 g (100%) of the title compound as a yellowpowder. ¹H-NMR (DMSO-d₆; 400 MHz): δ 9.51 (s, 1H), 7.90 (d, 1H, J=8.8Hz), 7.78 (d, 1H, J=3.8 Hz), 7.45 (d, H, J=3.8 Hz), 6.80 (d, 1H, J=2.3Hz), 6.72 (dd, 1H, J=2.6, 8.8 Hz), 3.35 (m, 4H, obscured by solvent),2.93 (br s, 4H), 2.81-2.78 (m, 4H), 2.48 (s, 3H), 1.68 bs, 4H),1.55-1.54 (m, 2H); Mass spectrum (ESI, m/z): Calcd. for C₂₂H₂₇N₅O₂,394.2 (M+1), found 394.1.

Example 314-[4-[(5-Cyano-furan-2-carbonyl)-amino]-3-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

a) 1-(5-Chloro-2-nitro-phenyl)-2,5-dimethyl-1H-pyrrole

To a solution of 5-chloro-2-nitrophenylamine (200 mg, 1.15 mmol) andhexane-2,5-dione (326 μL, 2.78 mmol) in THF (3 mL) was added 1 drop ofconc H₂SO₄. Toluene (3 mL) was then added and the reaction was allowedto stir at 120° C. overnight. At this time the reaction was diluted withCH₂Cl₂ (50 mL), washed with H₂O (2×25 mL), dried (Na₂SO₄) andconcentrated in vacuo. Purification by preparative thin layerchromatography (50% EtOAc-hexane) afforded 73 mg (25%) of the titlecompound as a tan solid. ¹H-NMR (CDCl₃; 400 MHz): δ 7.96 (d, 1H, J=8.7Hz), 7.59-7.54 (m, 1H), 7.39 (d, 1H, J=2.0 Hz), 5.92 (s, 2H), 1.97 (s,6H);

b)4-[3-(2,5-Dimethyl-pyrrol-1-yl)-4-nitro-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

To a stirred solution of1-(5-chloro-2-nitro-phenyl)-2,5-dimethyl-1H-pyrrole (73 mg, 0.29 mmol,as prepared in the previous step) in DMF (2 mL) was addedpiperazine-1-carboxylic acid tert-butyl ester (542 mg, 2.9 mmol) and theresult was heated to 90° C. for 18 h. The reaction a diluted with EtOAc(50 mL), washed with H₂O (2×25 mL), dried (Na₂SO₄) and concentrated invacuo. The residue was chromtographed on a SPE column (5 g, SiO₂) toafford 35 mg (30%) of the title compound as a brown solid. ¹H-NMR(CDCl₃; 400 MHz): δ 8.13 (d, 1H, J=9.3 Hz), 6.91-6.88 (m, 1H), 6.66 (s,1H), 5.93 (s, 2H), 3.63-3.60 (m, 4H), 3.42-3.40 (m, 4H), 1.97 (s, 6H),1.48 (s, 9H).

c)4-[4-Amino-3-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

Using a procedure similar to Example 23, step (a),4-[3-(2,5-dimethyl-pyrrol-1-yl)-4-nitro-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (35 mg, 0.08 mmol) was stirred in MeOH in thepresence of 5% Pd—C (20 mg) to afford 30 mg (100%) of the title compoundas an oil. Mass spectrum (ESI, m/z): Calcd. for C₂₁H₃₀N₄O₂, 371.2 (M+H),found 371.1.

d)4-[4-[(5-Cyano-furan-2-carbonyl)-amino]-3-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

Using a procedure similar to Example 4, step (c),4-[4-amino-3-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (30 mg, 0.8 mmol) was allowed to react with5-cyano-furan-2-carbonyl chloride (25 mg, 0.16 mmol) in the presence ofDIEA (276 mg, 1.7 mmol) to afford 14.9 mg (38%) of the title compound asa yellow solid. 1H-NMR (CDCl₃, 400 MHz):

8.43 (d, 1H, J=9.3 Hz), 7.25 (s, 1H), 7.10-7.13 (m, 2H), 7.03-7.06 (m,1H), 6.89 (s, 1H), 6.06 (s, 2H), 3.62-3.61 (m, 4H), 3.18-3.17 (m, 4H),1.96 (s, 6H), 1.48 (s, 9H); Mass spectrum (ESI, m/z): Calcd. forC₂₇H₃₁N₅O₄, 390.1 (M-BOC+2H), found 390.1.

Example 324-[4-(4-Methyl-piperazin-1-yl)-2-piperidin-1-yl-phenylcarbamoyl]-oxazole-2-carboxylicacid methyl ester

a) 2-Cyano-oxazole-4-carboxylic acid ethyl ester

To a solution of 2-formyl-oxazole-4-carboxylic acid ethyl ester (Paneket al. J. Org. Chem., 6496, (1996)) (171 mg, 1.11 mmol) in MeOH (3 mL)was added NH₂OH (50% wt. H₂O, 161 μL, 2.4 mmol). The reaction wasallowed to stir for 2 h, and then concentrated in vacuo. The crude oximewas treated with acetic anhydride (4 mL) and heated with stirring at150° C. for 24 h. The acetic anhydride was removed under vacuo, and thecrude material was purified by preparative thin layer chromatography(60% ether-hexanes) to afford 56 mg (31%) of the title compound as anoff-white solid. ¹H-NMR (CDCl₃; 400 MHz): δ 8.40 (s, 1H), 4.46 (q, 2H,J=7.1 Hz), 1.43 (t, 3H, J=7.1 Hz).

b)4-[4-(4-Methyl-piperazin-1-yl)-2-piperidin-1-yl-phenylcarbamoyl]-oxazole-2-carboxylicacid methyl ester

To a stirred solution of 2-cyano-oxazole-4-carboxylic acid ethyl ester(60 mg, 0.36 mmol, as prepared in the previous step) in 3 mL of THF-MeOH(1/1, v/v) was added 6N NaOH (365 μL, 2.19 mmol). The reaction was thenacidified to pH=4 with 6N HCl, and extracted with EtOAc (2×20 mL). Theorganic extracts were dried (Na₂SO₄) and concentrated in vacuo to afford46 mg of 2-oxazole-2,4-dicarboxylic acid 2-methyl ester. The acid inCH₂Cl₂ (3 mL) was treated with oxalyl chloride (34 mL, 0.39 mmol) andallowed to stir for 30 min. At this time the solvent was removed invacuo, and the crude acid chloride was dissolved in CH₂Cl₂ (3 mL) andadded via cannula to a stirring solution of4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenylamine (73 mg, 0.26mmol) in CH₂Cl₂ (3 mL). At this time DIEA (122 μL, 0.700 mmol) was addedand the reaction was allowed to stir overnight. Using a workup proceduresimilar to Example 2 afforded 56 mg (40%) of the title compound as ayellow solid. ¹H-NMR (CDCl₃; 400 MHz):

9.92 (s, 1H), 8.39 (s, 1H), 8.32 (d, 1H, J=8.9 Hz), 6.77 (d, 1H, J=2.6Hz), 6.71 (dd, 1H, J=2.6, 8.8 Hz), 4.12 (s, 3H), 3.21-3.18 (m, 4H),2.87-2.84 (m, 4H), 2.61-2.58 (m, 4H), 2.36 (s, 3H), 1.88-1.83 (m, 4H),1.63 (br s, 2H); Mass spectrum (ESI, m/z): Calcd. for C₂₁H₂₆N₆O₂, 428.2(M+H), found 428.2

Example 33 5-Cyano-furan-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amidedihydrochloride

a) 1-(5-Bromo-2-nitro-phenyl)-4-methyl-piperidine

A solution of 4-bromo-2-fluoro-phenylamine (3.00 g, 15.8 mmol) in 15 mLof DCM is added dropwise to a suspension of 3-chloroperoxybenzoic acid(19 g, 57-86%) in 200 mL of DCM at −10° C. and the mixture is allowed toattain RT and stirred for 10 h. The reaction is then washed withsaturated aqueous NaHCO₃ (2×150 mL) and brine (100 mL), and the organiclayer dried over Na₂SO₄ and evaporated. MeOH (10 mL) was then added tothe crude residue to precipitate a white solid that was removed byfiltration and the filtrate was concentrated to give4-bromo-2-fluoro-1-nitro-benzene. This product was dissolved in 100 mLof DCM, cooled to 0° C., and 4-methylpiperidine (5.00 g, 50.8 mmol) wasadded and the solution was stirred for 10 h at RT. The reaction wasdiluted with 100 mL of DCM, washed with brine (3×100 mL), and theorganic layer dried over Na₂SO₄ and concentrated. The crude oil waspurified by elution from a 20-g solid phase extraction (SPE) cartridge(silica) with 50% DCM/hexanes to give 3.4 g (72%) of the title compoundas a yellow oil: Mass spectrum (ESI, m/z): Calcd. for C₁₂H₁₅BrN₂O₂,299.0 (M+H), found 299.1.

b)1-[5-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2-nitro-phenyl]-4-methyl-piperidine

To a solution of 1-(5-bromo-2-nitro-phenyl)-4-methyl-piperidine (0.60 g,2.0 mmol) (as prepared in the previous step) in 5 mL of methanol wasadded bis(neopentylglycolato) diboron (0.68 g, 3.0 mmol), potassiumacetate (0.40 g, 4.0 mmol), and Pd(dppf)Cl₂ (0.07 g, 5 mol %) and thereaction heated for 5 h at 60° C. The solution was concentrated and theproduct eluted from a 20-g SPE cartridge (silica) with 100% DCM to give0.46 g (70%) of the title compound as a red oil. ¹H-NMR (400 MHz,CDCl₃): δ 7.71 (d, 1H), 7.59 (d, 1H), 7.40 (dd, 1H), 3.80 (s, 4H), 3.26(m, 2H), 2.82 (m, 2H), 1.74 (m, 2H), 1.48 (m, 3H), 1.40 (s, 6H), 1.0 (d,3H).

c)4-[3-(4-Methyl-piperidin-1-yl)-4-nitro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

A flask is charged with1-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-nitro-phenyl]-4-methyl-piperidine(0.090 g, 0.27 mmol) (as prepared in the previous step),4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (0.090 g, 0.27 mmol) (Synthesis, 993, (1991)), LiCl(0.022 g, 0.54 mmol), Pd(PPh₃)₄ (0.015 g, 5 mol %), 2 M Na₂CO₃ (0.34mL), DME (0.80 mL) and heated at 80° C. for 30 min. The reaction wasdiluted with EtOAc (10 mL) and washed with saturated aqueous NaHCO₃(2×10 mL) and brine (10 mL), and the organic layer dried over Na₂SO₄ andevaporated. The crude product was eluted from a 10-g SPE cartridge(silica) with 10% EtOAc/hexane to give 0.080 g (74%) of the titlecompound as a light yellow oil. Mass spectrum (ESI, m/z): Calcd. forC₂₂H₃₁N₃O₄, 402.2 (M+H), found 402.1.

d)4-[4-Amino-3-(4-methyl-piperidin-1-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

A flask charged with4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (0.080 g, 0.20 mmol) (as prepared in the previousstep), ammonium chloride (0.10 g, 2.0 mmol), iron powder (0.055 g, 10mmol), EtOH (1 mL) and water (0.5 mL) was heated at 80° C. for 30 min.The reaction was filtered though Celite, concentrated and eluted from a10-g SPE cartridge (silica) with 20% EtOAc/hexane to give 0.040 g (50%)of the title compound as a yellow oil. ¹H-NMR (400 MHz, CDCl₃): δ 7.08(d, 1H), 6.97 (dd, 1H), 6.72 (d, 1H), 5.89 (m, 1H), 4.75 (br s, 2H),4.08 (m, 2H), 3.63 (m, 2H), 3.12 (m, 2H), 2.62 (m, 2H), 2.50 (m, 2H),1.78 (m, 2H), 1.52 (s, 9H), 1.38 (m, 3H), 1.00 (d, 3H).

e) 5-Cyano-furan-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amidedihydrochloride

A flask was charged with 5-cyano-furan-2-carboxylic acid (0.015 g, 0.10mmol) (as prepared in Example 1), DCM (1 mL), DMF (5 μL), and oxalylchloride (10 μL, 0.11 mmol) and stirred at 25° C. for 1 h and thenconcentrated. The resulting 5-cyano-furan-2-carbonyl chloride wasdissolved in DCM (1 mL) and added to a solution of4-[4-amino-3-(4-methyl-piperidin-1-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (0.040 g, 0.10 mmol) (as prepared in the previousstep) and NEt₃ (25 μL, 0.15 mmol) in DCM (1 mL) at 0° C. The solutionwas allowed to attain RT and stirred for 10 h. The intermediate BOCprotected compound was eluted from a 5-g SPE cartridge (silica) with 20%EtOAc/hexane, and then dissolved in DCM (1 mL) and TFA (0.30 mL) andstirred at 25° C. for 30 min. The reaction was concentrated and purifiedby RP-HPLC (C18), eluting with a linear gradient of 40% CH₃CN to 70%CH₃CN in 0.1% TFA/H₂O over 10 min to give the title compound as a di-TFAsalt. This product was then eluted from a 10-g column of BioRad AG-2X8resin (chloride ion form) with methanol to give 0.017 g (37%) of thetitle compound. ¹H-NMR (400 MHz, DMSO-d₆): δ 9.81 (s, 1H), 9.40 (br s,2H), 8.18 (d, 1H), 7.82 (d, 1H), 7.50 (d, 1H), 7.36 (s, 1H), 7.28 (d,1H), 6.22 (m, 1H), 3.76 (m, 2H), 3.46 (3, 3H), 2.98 (m, 2H), 2.74 (m,6H), 1.82 (m, 2H), 1.50 (m, 3H), 1.00 (d, 3H), Mass spectrum (ESI, m/z):Calcd. for C₂₃H₂₆N₄O₂, 391.2 (M+H), found 391.2.

Example 34 5-Cyano-furan-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amidebis(trifluoracetic acid salt)

a)4-[4-Amino-3-(4-methyl-piperidin-1-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester

A solution of4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (0.090 g, 0.22 mmol) (as prepared in Example 33,step (d)) in methanol (2 mL) was hydrogenated over 10% Pd/C at 12 psifor 2 h. The solution was filtered and concentrated to give 0.085 g(100%) of the title compound as an oil. Mass spectrum (ESI, m/z): Calcd.for C₂₂H₃₅N₃O₂, 374.3 (M+H), found 374.1.

b) 5-Cyano-furan-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amidebis(trifluoroacetic acid salt)

The title compound was obtained by coupling4-[4-amino-3-(4-methyl-piperidin-1-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester (as prepared in the previous step) to5-cyano-furan-2-carboxylic acid (as prepared in Example 1) and BOCdeprotection according to the procedure in Example 33, step (e). Thetitle compound was purified by RP-HPLC (C18), eluting with a lineargradient of 30% to 50% CH₃CN in 0.1% TFA/H₂O over 12 min. ¹H-NMR (400MHz, DMSO-d₆): δ 9.72 (s, 1H), 9.58 (br s, 1H), 9.28 (br s, 1H), 8.18(d, 1H), 7.82 (d, 1H), 7.48 (d, 1H), 7.12 (s, 1H), 7.04 (d, 1H), 3.40(m, 2H), 3.00. (m, 4H), 2.80 (m, 3H), 2.95 (m, 2H), 1.80 (m, 4H), 1.50(m, 3H), 1.02 (d, 3H). Mass spectrum (ESI, m/z): Calcd. for C₂₃H₂₈N₄O₂,393.2 (M+H), found 393.2.

Example 35 4-Cyano-1H-pyrrole-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amidebis(trifluoracetic acid salt)

The title compound was obtained by coupling4-[4-amino-3-(4-methyl-piperidin-1-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester (as prepared in Example 34, step (a)) and4-cyano-1H-pyrrole-2-carboxylic acid (as prepared in Example 2) followedby BOC deprotection according to the procedure in Example 33, step (e).The title compound was purified by RP-HPLC (C18), eluting with a lineargradient of 30% to 50% CH₃CN in 0.1% TFA/H₂O over 12 min. ¹H-NMR (400MHz, CH₃OD): δ 7.80 (d, 2H), 7.70 (s, 1H), 7.48 (s, 1H), 7.38 (m, 2H),3.60. (m, 2H), 3.44 (m, 2H), 3.20 (m, 4H), 3.02 (m, 1H), 2.20-1.50 (m,9H), 1.08 (d, 3H). Mass spectrum (ESI, m/z): Calcd. for C₂₃H₂₉N₅O, 392.2(M+H), found 392.2.

Example 36 5-Cyano-furan-2-carboxylic acid[4-(1-acetyl-piperidin-4-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide

A flask was charged with 5-cyano-furan-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amide (0.035 g, 56μmol) (as prepared in Example 34, step (b)), NEt₃ (31.0 μL, 225 μmol),acetic anhydride (6.5 μL, 62 μmol), and DCM (0.5 mL) and stirred at RTfor 1 h. The title compound was eluted from a 10-g SPE cartridge(silica) with 5% MeOH/DCM to give 18 mg (75%) of a white solid. ¹H-NMR(400 MHz, CDCl₃): δ 9.78 (s, 1H), 8.34 (d, 1H), 7.24 (m, 2H), 7.01 (m,2H), 4.80 (m, 2H), 3.96. (m, 2H), 3.20 (t, 1H), 2.98 (m, 2H), 2.70 (m,4H), 2.28 (s, 3H), 1.88 (m, 4H), 1.60 (m, 5H), 1.10 (d, 3H). Massspectrum (ESI, m/z): Calcd. for C₂₅H₃₀N₄O₃, 435.2 (M+H), found 435.2.

Example 37 5-Cyano-1H-imidazole-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amidetrifluoroacetic acid salt

a) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid [4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide

A flask was charged with4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (0.043 g, 0.14 mmol) (as prepared in Example 3, step(d)), 4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenylamine (0.028 g,0.10 mmol) (as prepared in Example 5, step (b)), EDCI (0.030 g, 0.16mmol), DMAP (0.012 g, 0.010 mmol), and DMF (0.5 mL) and was stirred for12 h at RT and then 1 h at 60° C. The reaction mixture was loaded on a10-g SPE cartridge (silica) and eluted with 10% MeOH/DCM to give 0.030 g(57%) of title compound. Mass spectrum (ESI, m/z): Calcd. forC₂₇H₄₁N₇O₂Si, 524.3 (M+H), found 524.1.

b) 5-Cyano-1H-imidazole-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amidetrifluoroacetic acid salt

To a flask charged with4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid [4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide (0.030g, 0.060 mmol) (as prepared in the previous step) was added 6N HCl (0.3mL) and EtOH (0.6 mL) and the solution heated at 70° C. for 20 min. Thereaction was concentrated and the title compound was purified by RP-HPLC(C18), eluting with 10-70% CH₃CN in 0.1% TFA/H₂O over 15 min to give0.020 g (69%) the title compound. ¹H-NMR (400 MHz, DMSO-d₆): δ 14.28 (s,1H), 9.84 (s, 1H), 9.65 (br s, 1H), 8.38 (s, 1H), 8.16 (d, 1H), 6.92 (d,1H), 6.80 (dd, 1H), 3.86 (m, 2H), 3.54. (m, 2H), 3.18 (m, 1H), 2.90 (m,9H), 1.78 (m, 4H), 1.62 (m, 2H). Mass spectrum (ESI, m/z): Calcd. forC₂₁H₂₇N₇O, 394.2 (M+H), found 394.2.

Example 38 3H-Imidazole-4-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amidebis(trifluoroacetic acid salt)

a) 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxyate sodiumsalt

To a solution of1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylic acidmethyl ester (0.42 g, 1.6 mmol) (as prepared in Example 40, step (a)) inMeOH (3.0 mL) was added 1N NaOH (1.6 mL) and mixture was stirred for 8 hat RT. The reaction was concentrated to give 0.43 g (100%) of the titlecompound as a white solid. Mass spectrum (ESI, m/z): Calcd. forC₁₀H₁₈N₂O₃Si, 243.1 (M+H), found 243.1.

b) 3H-Imidazole-4-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amidebis(trifluoroacetic acid salt)

The title compound was prepared by coupling1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylate sodiumsalt (as prepared in the previous step) and4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenylamine (as prepared inExample 5, step (b)) according to the procedure in Example 37, step (a)followed by SEM deprotection according to the procedure in Example 37,step (b). The title compound was purified by RP-HPLC (C18), eluting with10-35% CH₃CN in 0.1% TFA/H₂O over 12 min. ¹H-NMR (400 MHz, CH₃OD): δ8.72 (s, 1H), 8.22 (s, 1H), 7.62 (d, 1H), 7.34 (d, 1H), 7.18 (d, 1H),4.02 (m, 2H), 3.74 (m, 2H), 3.60 (m, 4H), 3.28 (m, 4H), 3.02 (s, 3H),2.04 (m, 4H), 1.78 (m, 2H). Mass spectrum (ESI, m/z): Calcd. forC₂₀H₂₈N₆O, 369.2 (M+H), found 369.2.

Example 39 1H-Imidazole-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amidebis(trifluoroacetic acid salt)

1H-Imidazole-2-carboxylic acid was coupled to4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenylamine (as prepared inExample 5, step (b)) according to the procedure in Example 37, step (a).The title compound was purified by RP-HPLC (C18), eluting with 10-35%CH₃CN in 0.1% TFA/H₂O over 12 min. ¹H-NMR (400 MHz, CH₃OD): δ 8.04 (d,1H), 7.32 (s, 2H), 7.02 (d, 1H), 6.92 (d, 1H), 3.88 (m, 2H), 3.66 (m,2H), 3.30 (m, 2H), 3.08 (m, 6H), 3.02 (s, 3H), 1.92 (m, 4H), 1.70 (m,2H). Mass spectrum (ESI, m/z): Calcd. for C₂₀H₂₈N₆O, 369.2 (M+H), found369.2.

Example 40 3H-Imidazole-2,4-dicarboxylic acid 2-amide4-{[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide}trifluoroaceticacid salt

a) 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylic acidmethyl ester

A flask charged with 1H-imidazole-4-carboxylic acid methyl ester (0.54g, 4.3 mmol), 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) (1.0 mL,5.6 mmol), K₂CO₃ (1.4 g, 10.4 mmol), and DMF (7 mL) was stirred for 10 hat 80° C. The mixture was diluted with EtOAc (20 mL) and washed withwater (20 mL) and brine (20 mL) and the organic layer dried over MgSO₄and concentrated. The title compound was eluted from a 20-g SPEcartridge (silica) with 50% EtOAc/hexane to give 0.66 g (60%) of acolorless oil. Mass spectrum (ESI, m/z): Calcd. for C₁₁H₂₀N₂O₃Si, 257.1(M+H), found 257.0.

b) 2-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylicacid methyl ester

To a solution of1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylic acidmethyl ester (0.43 g, 1.6 mmol) (as prepared in the previous step) inCCl₄ (10 mL) was added NBS (0.30 g, 1.7 mmol) and AIBN (cat) and themixture heated at 60° C. for 4 h. The reaction was diluted with EtOAc(30 ml) and washed with satd NaHCO₃ (2×30 mL) and brine (30 mL) and theorganic layer concentrated. The title compound was eluted from a 20-gSPE cartridge (silica) with 50% EtOAc/hexane to give 0.40 g (71%) of ayellow solid. Mass spectrum (ESI, m/z): Calcd. for C₁₁H₁₉BrN₂O₃Si,335.0/337.0 (M+H), found 335.0/337.0.

c)2-Formyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylicacid methyl ester

To a solution of2-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylicacid methyl ester (0.25 g, 0.74 mmol) (as prepared in the previous step)in THF (3 mL) at −40° C. was added dropwise a solution of 2M i-PrMgCl inTHF (0.37 mL, 0.74 mmol). The reaction was allowed to stir for 10 min at−40° C. and then cooled to −78° C. and DMF (0.3 mL) was added. Thereaction was allowed to attain RT and stirred for 1 h. The reaction wasquenched with saturated NH₄Cl, diluted with EtOAc (10 mL) and washedwith brine (2×10 mL) and the organic layer was concentrated. The titlecompound was eluted from a 10-g SPE cartridge (silica) with 50%EtOAc/hexane to give 0.11 g (53%) of a colorless oil. Mass spectrum(ESI, m/z): Calcd. for C₁₂H₂₀N₂O₄Si, 285.1 (M+H), found 284.7.

d) 2-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylicacid methyl ester

To a solution of2-formyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylicacid methyl ester (0.11 g, 0.38 mmol) (as prepared in the previous step)in methanol (2 mL) was added a 50% aqueous hydroxylamine solution (30μL) and the reaction stirred for 3 h at RT and then concentrated. Theresidue was dissolved in DCM (2 mL), pyridine (0.13 mL), andtrifluoroacetic anhydride (0.17 mL, 1.1 mmol) was added and the reactionstirred for 10 h at RT. The reaction was diluted with EtOAc (10 mL) andwashed with satd. NaHCO₃ (2×10 mL) and the organic layer dried overNa₂SO₄ and then concentrated. The title compound was eluted from a 10-gSPE cartridge (silica) with 30% EtOAc/hexane to give 0.085 g (76%) of acolorless oil. ¹H-NMR (400 MHz, CDCl₃): δ 7.99 (s, 1H), 5.50 (s, 2H),3.92 (s, 3H), 3.58 (m, 2H), 0.94 (m, 214), 0.00 (s, 9H).

e) 3H-Imidazole-2,4-dicarboxylic acid 2-amide4-{[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide}trifluoroaceticacid salt

To a solution of2-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylicacid methyl ester (85 mg, 0.30 mmol) (as prepared in the previous step)in EtOH was added 6M KOH (50 μL) and the reaction stirred for 1 h at RTand then concentrated. The residue was dissolved in DMF (1 mL) and DMAP(34 mg, 0.30 mmol), EDCI (80 mg, 0.42 mmol) and4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenylamine (75 mg, 0.30mmol) (as prepared in Example 5, step (b)) were added and the reactionstirred for 10 h at RT. The reaction was diluted with EtOAc (10 mL) andwashed with brine (2×10 mL) and the organic layer dried (Na₂SO₄) andconcentrated. The residue was dissolved in EtOH (0.3 mL) and 6N HCl (0.3mL) and heated to 80° C. for 1 h. The reaction was concentrated and thetitle compound was purified by RP-HPLC (C18) eluting with 10-35% CH₃CNin 0.1% TFA/H₂O over 12 min to give 33 mg (21%) of the title compound.¹H-NMR (400 MHz, CH₃OD): δ 8.00 (s, 1H), 7.72 (d, 1H), 7.22 (s, 1H),7.13 (d, 1H), 3.98 (m, 2H), 3.68 (m, 2H), 3.46 (m, 4H), 3.32 (m, 2H),3.18 (m, 2H), 3.00 (s, 3H), 1.98 (m, 4H), 1.76 (m, 2H). Mass spectrum(ESI, m/z): Calcd. for C₂₁H₂₉N₇O₂, 412.2 (M+H), found 412.2.

Example 41 1H-Imidazole-2-carboxylic acid[3-chloro-4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amidebis(trifluoroacetic acid salt)

A flask was charged with 1H-imidazole-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide (14 mg,0.020 μmmol) (as prepared in Example 39), N-chlorosuccinimide (6.0 mg,0.020 μmol), acetic acid (25 μL), and CH₃CN (0.5 mL) and heated at 80°C. for 1 h. The reaction was concentrated and purified by RP-HPLC (C18),eluting with 10-35% CH₃CN in 0.1% TFA/H₂O over 12 min to give 5 mg (36%)of the title compound. ¹H-NMR (400 MHz, CH₃OD): δ 8.42 (s, 1H), 7.32 (s,2H), 7.06 (s, 1H), 3.68 (m, 2H), 3.54. (m, 2H), 3.38 (m, 2H), 3.12 (m,2H), 3.02 (s, 3H), 2.92 (m, 4H), 1.92 (m, 4H), 1.70 (m, 2H). Massspectrum (ESI, m/z): Calcd. for C₂₀H₂₇ClN₆O, 403.2 (M+H), found 403.1.

Example 424-[4-[2-(4-Cyano-1H-pyrrol-2-yl)-2-oxo-ethyl]-3-(4-methyl-piperidin-1-yl)-phenyl]-piperidine-1-carboxylicacid (2-dimethylamino-ethyl)-amide

To a mixture of 4-cyano-1H-pyrrole-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amidebis(trifluoroacetic acid salt) (as prepared in Example 35, 20.0 mg,0.0323 mmol) and anh K₂CO₃ (22 mg, 0.16 mmol) in 0.50 mL of DMF at −78°C. was added a solution of triphosgene (3.8 mg, 0.013 mmol) in 0.5 mL ofDCM under Ar. The mixture was warmed to 0° C. and stirred for 3 min,then cooled to −78° C. again. N1,N1-dimethyl-ethane-1,2-diamine (14 μL,0.13 mmol) was added. The solution was warmed to RT and stirred for 16 hunder Ar. Treated with 30 mL of EtOAc, the mixture was washed with H₂O(3×10 mL), brine (10 mL) and dried (Na₂SO₄). Removal of the solvent invacuo followed by flash chromatography of the residue on silica gel(0-10% MeOH/DCM) gave 7.5 mg (46%) of the title compound as a colorlessoil: ¹H-NMR (CDCl₃; 400 MHz): δ 11.0 (s, 1H), 9.15 (s, 1H), 8.28 (d, 1H,J=8.4 Hz), 7.46 (d, 1H, J=1.2 Hz), 7.03 (d, 1H, J=1.9 Hz), 6.98 (dd, 1H,J=8.4, 1.2 Hz), 6.86 (d, 1H, J=1.9 Hz), 5.47 (s, 1H), 4.10 (d, 2H,J=12.9 Hz), 3.40 (ddd, 2H, J=6.1, 5.2, 5.1 Hz), 2.94 (d, 2H, J=11.6 Hz),2.83 (td, 2H, J=12.9, 1.9 Hz), 2.71 (td, 2H, J=11.7, 2.0 Hz), 2.53-2.66(m, 3H), 2.33 (s, 6H), 1.77-1.89 (m, 4H), 1.53-1.68 (m, 3H), 1.33-1.44(m, 2H), 1.08 (d, 3H, J=6.5 Hz). Mass spectrum (ESI, m/z): Calcd. forC₂₈H₃₉N₇O₂, 506.3 (M+H), found 506.2.

Example 43 4-Cyano-1H-pyrrole-2-carboxylic acid[4-[1-(imidazole-1-carbonyl)-piperidin-4-yl]-2-(4-methyl-piperidin-1-yl)-phenyl]-amide

To a mixture of 4-cyano-1H-pyrrole-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amidebis(trifluoroacetic acid salt) (as prepared in Example 35, 20.0 mg,0.0320 mmol) and anh Na₂CO₃ (6.8 mg, 0.065 mmol) in 0.30 mL of DMF wasadded carbonyldiimidazole (11 mg, 0.068 mmol) in 0.3 mL of THF at RT.The mixture was stirred at RT for 2 h. Treated with 20 mL of EtOAc, themixture was washed with H₂O, brine and dried with Na₂SO₄. Removal of thesolvent under reduced pressure followed by flash chromatography of theresidue on silica gel (1-5% MeOH/DCM) gave 14 mg (86%) of the titlecompound as a white solid: ¹H-NMR (CDCl₃; 400 MHz): δ 10.7 (s, 1H), 9.16(s, 1H), 8.33 (d, 1H, J=8.3 Hz), 7.95 (s, 1H), 7.47 (s, 1H), 7.13 (s,1H), 7.06 (s, 1H), 7.03 (s, 1H), 6.88 (s, 1H), 4.28 (d, 2H, J=12.9 Hz),3.16 (d, 2H, J=12.0 Hz), 2.97 (d, 2H, J=11.6 Hz), 2.71-2.84 (m, 3H),1.99 (d, 2H, J=12.1 Hz), 1.87 (d, 2H, J=12.1 Hz), 1.71-1.83 (m, 2H),1.65 (s, 1H), 1.54-1.65 (m, 1H), 1.34-1.48 (m, 2H), 1.10 (d, 3H, J=6.5Hz). Mass spectrum (ESI, m/z): Calcd. for C₂₇H₃₁N₇O₂, 486.2 (M+H), found486.0.

Example 44 4-Cyano-1H-pyrrole-2-carboxylic acid{2-(4-methyl-piperidin-1-yl)-4-[1-(pyridine-3-carbonyl)-piperidin-4-yl]-phenyl}-amide

A mixture of 4-cyano-1H-pyrrole-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amidebis(trifluoroacetic acid salt) (as prepared in Example 35, 25.0 mg,0.0400 mmol), nicotinoyl chloride (10.8 mg, 0.0600 mmol) and anh Na₂CO₃(21.0 mg, 0.200 mmol) in 1 mL of DMF was stirred at RT for 2 days.Treated with 30 mL of EtOAc, the mixture was washed with H₂O (3×10 mL),brine (10 mL) and dried (Na₂SO₄). Removal of the solvent under reducedpressure followed by flash chromatography of the residue on silica gel(1-3% MeOH/DCM) gave 19.6 mg (98%) of the title compound as a whitesolid: ¹H-NMR (CDCl₃; 400 MHz): δ 10.67, (s, 1H), 9.17 (s, 1H), 8.74 (d,1H, J=1.6 Hz), 8.69 (dd, 1H, J=4.5, 1.6 Hz), 8.32 (d, 1H, J=8.4 Hz),7.82 (ddd, 1H, J=7.7, 1.9, 1.9 Hz), 7.47 (dd, 1H, J=3.3, 1.2 Hz), 7.40(dd, 1H, J=8.0, 4.9 Hz), 7.07 (d, 1H, J=1.9 Hz), 7.04 (dd, 1H, J=8.4,1.9 Hz), 6.87 (s, 1H), 4.90 (s, 1H), 3.87 (s, 1H), 3.22 (s, 1H),2.69-3.00 (m, 6H), 1.53-2.06 (m, 7H), 1.35-1.46 (m, 2H), 1.00 (d, 3H,J=6.5 Hz). Mass spectrum (ESI, m/z): Calcd. for C₂₉H₃₂N₆O₂, 497.3 (M+H),found 497.2.

Example 45 4-Cyano-1H-pyrrole-2-carboxylic acid[4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-2-(4-methyl-piperidin-1-yl)-phenyl]-amide

A mixture of 4-cyano-1H-pyrrole-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amidebis(trifluoroacetic acid salt) (as prepared in Example 35, 20.0 mg,0.0320 mmol) in 2 mL of 1:1 1N NaOH/MeOH solution was stirred at RT for1 h. Treated with 20 mL of EtOAc, the mixture was washed with H₂O (3×5mL). The aqueous layers were extracted with EtOAc (2×5 mL). The combinedorganic layers were washed with brine (10 mL), dried (Na₂SO₄) andconcentrated in vacuo to give a white solid. The solid was added to amixture of N,N-dimethylglycine (5.0 mg, 0.048 mmol), EDCI (9.2 mg, 0.048mmol), HOBt (6.5 mg, 0.048 mmol) and DIEA (16.7 μL, 0.096 mmol) in 0.80mL of DCM. The resulting mixture was stirred at RT for 4 h. Treated with30 mL of EtOAc, the mixture was washed with H₂O (3×5 mL), brine (5 mL)and dried (Na₂SO₄). Removal of the solvent under reduced pressurefollowed by flash chromatography of the residue on silica gel (1-5%MeOH/DCM) gave 12 mg (78%) of the title compound as a white solid:¹H-NMR (CDCl₃; 400 MHz): δ 11.0 (s, 1H), 9.17 (s, 1H), 8.31 (d, 1H,J=8.4 Hz), 7.48 (d, 1H, J=1.3 Hz), 7.05 (d, 1H, J=1.8 Hz), 7.01 (dd, 1H,J=8.4, 1.8 Hz), 6.87 (d, 1H, J=1.3 Hz), 4.77 (d, 1H, J=13.3 Hz), 4.24(d, 1H, J=13.3 Hz), 3.07-3.25 (m, 3H), 2.96 (d, 2H, J=11.8 Hz),2.61-2.77 (m, 4H), 2.33 (s, 6H), 1.82-1.94 (m, 4H), 1.53-1.70 (m, 3H),1.32-1.47 (m, 2H), 1.09 (d, 3H, J=6.5 Hz). Mass spectrum (ESI, m/z):Calcd. for C₂₇H₃₆N₆O₂, 477.3 (M+H), found 477.2.

Example 46 4-Cyano-1H-pyrrole-2-carboxylic acid(2-(4-methyl-piperidin-1-yl)-4-[1-(2,2,2-trifluoroethyl)-piperidin-4-yl]-phenyl)-amide

A mixture of 4-cyano-1H-pyrrole-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amidebis(trifluoroacetic acid salt) (as prepared in Example 35, 25 mg, 0.040mmol), trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (9.8 mg,0.042 mmol) and Na₂CO₃ (21 mg, 0.20 mmol) in 1 mL of DMF was stirred atRT for 8 h. Treated with 30 mL of EtOAc, the mixture was washed with H₂O(2×10 mL), brine (10 mL) and dried (Na₂SO₄). Removal of the solventunder reduced pressure followed by flash chromatography of the residueon silica gel (40% EtOAc/hexane) gave 11 mg (55%) of the title compoundas a white solid: ¹H-NMR (CDCl₃; 400 MHz): δ 10.7 (s, 1H), 9.20 (s, 1H),8.29 (d, 1H, J=8.4 Hz), 7.47 (dd, 1H, J=3.1, 1.4 Hz), 7.10 (d, 1H, J=1.8Hz), 7.04 (dd, 1H, J=8.4, 1.8 Hz), 6.87 (dd, 1H, J=3.1, 1.4 Hz),2.90-3.14 (m, 6H), 2.72 (dd, 2H, J=11.5, 11.5 Hz), 2.41-2.52 (m, 3H),1.74-1.90 (m, 6H), 1.60 (br s, 1H), 1.34-1.44 (m, 2H), 1.09 (d, 3H,J=6.5 Hz). Mass spectrum (ESI, m/z): Calcd. for C₂₅H₃₀F₃N₅O, 474.2(M+H), found 474.1.

Example 47 4-Cyano-1H-imidazole-2-carboxylic acid[4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide

a) Trifluoromethanesulfonic acid 3,6-dihydro-2H-thiopyran-4-yl ester

A solution of tetrahydro-thiopyran-4-one (1.00 g, 8.61 mmol) in 10 ml ofTHF was added to a solution of LDA (2.0 M, 4.52 ml, 9.04 mmol) in 20 mlof THF at −78° C. under Ar. The mixture was warmed to RT and stirred for0.5 h, then cooled to −78° C. again. A solution ofN-phenyltrifluoromethanesulfonimide (3.42 g, 9.47 mmol) in 10 mL of THFwas added. The resulting mixture was warmed to RT and stirred for 0.5 hunder Ar. Treated with 200 ml of EtOAc, the mixture was washed with H₂O(3×50 mL), brine (50 mL) and dried (Na₂SO₄). Removal of the solventunder reduced pressure followed by flash chromatography of the residueon silica gel (hexane-3% EtOAc/hexane) gave 810 mg (38%) of the titlecompound as a colorless oil: ¹H-NMR (CDCl₃; 400 MHz): δ 6.01 (m, 1H),3.30 (m, 2H), 2.86 (dd, 2H, J=5.7, 5.7 Hz), 2.58-2.64 (m, 2H). Massspectrum (ESI, m/z): Calcd. for C₆H₇F₃O₃S₂, 249.0 (M+H), found 249.3.

b)1-[5-(3,6-Dihydro-2H-thiopyran-4-yl)-2-nitro-phenyl]-4-methyl-piperidine

To a mixture of1-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-nitro-phenyl]-4-methyl-piperidine(as prepared in Example 33, step (b), 60 mg, 0.18 mmol),trifluoromethanesulfonic acid 3,6-dihydro-2H-thiopyran-4-yl ester (asprepared in the previous step, 54 mg, 0.22 mmol), Pd(PPh₃)₄ (31 mg,0.027 mmol) and LiCl (15 mg, 0.36 mmol) in 1 mL of 1,4-dioxane was added2.0 M Na₂CO₃ aq solution (80 μL, 0.16 mmol). The resulting mixture wasstirred at 80° C. for 1 h, and then cooled to RT. Treated with 50 mL ofEtOAc, the mixture was washed with H₂O, brine and dried (Na₂SO₄).Removal of the solvent under reduced pressure followed by flashchromatography of the residue on silica gel (1% EtOAc/hexane) gave 56 mg(97%) of the title compound as a brown oil: ¹H-NMR (CDCl₃; 400 MHz): δ7.77 (d, 1H, J=8.6 Hz), 7.01 (d, 1H, J=1.8 Hz), 6.88 (dd, 1H, J=8.6, 1.8Hz), 6.24 (m, 1H), 3.34-3.37 (m, 2H), 3.26 (d, 2H, J=12.4 Hz), 2.89 (t,2H, J=5.7 Hz), 2.82 (td, 2H, J=12.0, 1.6 Hz), 2.64-2.69 (m, 2H), 1.70(dd, 2H, J=12.4, 2.1 Hz), 1.52 (m, 1H), 1.36-1.47 (m, 2H), 0.99 (d, 3H,J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C₁₇H₂₂N₂O₂S, 319.1(M+H), found 319.1.

c)1-[5-(1,1-Dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-2-nitro-phenyl]-4-methyl-piperidine

A mixture of 3-chloroperoxybenzoic acid (77 mg, 0.35 mmol, 77%) in 2 mLof DCM was added slowly to a solution of1-[5-(3,6-dihydro-2H-thiopyran-4-yl)-2-nitro-phenyl]-4-methyl-piperidine(as prepared in the previous step, 50 mg, 0.16 mmol) in 2 mL of DCM at−78° C. under Ar. The mixture was stirred at −78° C. for 0.5 h, and thenWarmed to RT. Treated with 2 mL of 10% Na₂SO₃ solution, the mixture wasstirred vigorously for 5 min. The mixture was treated with 30 mL ofEtOAc and 10 mL of H₂O. The aqueous layer was separated and the organiclayer was washed with saturated aq NaHCO₃ solution (10 mL), H₂O (10 mL)and dried (Na₂SO₄). Removal of the solvent under reduced pressurefollowed by flash chromatography of the residue on silica gel (0-2%EtOAc/DCM) gave 35 mg (64%) of the title compound as a yellow oil:¹H-NMR (CDCl₃; 400 MHz): δ 7.77 (d, 1H, J=8.6 Hz), 7.00 (d, 1H, J=1.9Hz), 6.88 (dd, 1H, J=8.6, 1.9 Hz), 5.93 (m, 1H), 3.83 (br s, 2H),3.24-3.30 (m, 4H), 3.11-3.17 (m, 2H), 2.83 (ddd, 2H, J=12.0, 12.0, 2.3Hz), 1.72 (dd, 2H, J=12.6, 2.3 Hz), 1.53 (m, 1H), 1.35-1.47 (m, 2H),1.00 (d, 3H, J=6.3 Hz). Mass spectrum (ESI, m/z): Calcd. forC₁₇H₂₂N₂O₄S, 351.1 (M+H), found 351.0.

d)4-(1,1-Dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-2-(4-methyl-piperidin-1-yl)-phenylamine

A mixture of1-[5-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-2-nitro-phenyl]-4-methyl-piperidine(as prepared in the previous step, 65 mg, 0.19 mmol) and 10% Pd/C (40mg) in 3 mL of MeOH was stirred at RT under H₂ (balloon pressure) for 1h. The Pd catalyst was removed by filtration on Celite and the filtratewas concentrated to give a white solid. Flash chromatography of thecompound on silica gel (5% EtOAc/DCM) gave 42 mg (70%) of the titlecompound as a white solid: ¹H-NMR (CDCl₃; 400 MHz): δ 6.82 (s, 1H), 6.76(d, 1H, J=8.2 Hz), 6.68 (d, 1H, J=8.2 Hz), 3.91 (s, 2H), 3.05-3.16 (m,6H), 2.67 (dddd, 2H, J=12.0, 12.0, 3.2, 3.2 Hz), 2.57 (dd, 2H, J=11.6,11.6 Hz), 2.36 (m, 2H), 2.14-2.23 (m, 2H), 1.71-1.79 (m, 2H), 1.51 (m,1H), 1.24-1.40 (m, 2H), 0.99 (d, 3H, J=6.6 Hz). Mass spectrum (ESI,m/z): Calcd. for C₁₇H₂₆N₂O₂S, 323.2 (M+H), found 323.2.

e) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-2-(4-methyl-piperidin-1-phenyl]-amide

To a mixture of4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-2-(4-methyl-piperidin-1-yl)-phenylamine(as prepared in the previous step, 16 mg, 0.050 mmol),4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium (as prepared in Example 3, step (d), 17 mg, 0.055 mmol) andPyBroP (35 mg, 0.075 mmol) in 1 mL of DCM was added DIEA (17 μL, 0.10mmol). The resulting mixture was stirred at RT for 20 h under Ar.Treated with 30 mL of EtOAc, the mixture was washed with H₂O (3×10 mL),brine (10 mL) and dried (Na₂SO₄). Removal of the solvent under reducedpressure followed by flash chromatography of the residue on silica gel(1-2% EtOAc/DCM) gave 19 mg (68%) of the title compound as a colorlessoil: ¹H-NMR (CDCl₃; 400 MHz): δ 10.4 (s, 1H), 8.29 (d, 1H, J=8.4 Hz),7.79 (s, 1H), 7.02 (d, 1H, J=1.9 Hz), 6.99 (dd, 1H, J=8.4, 1.9 Hz), 5.97(s, 2H), 3.67 (app t, 2H, J=8.3 Hz), 3.14 (m, 4H), 2.99 (d, 2H, J=12.0Hz), 2.67-2.80 (m, 3H), 2.40 (m, 2H), 2.22 (m, 2H), 1.79 (m, 2H),1.52-1.67 (m, 3H), 1.08 (d, 3H, J=5.9 Hz), 0.98 (app t, 2H, J=8.3 Hz),0.001 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C₂₈H₄₁N₅O₄SSi, 572.3(M+H), found 572.0.

f) 4-Cyano-1H-imidazole-2-carboxylic acid[4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide

A solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide(as prepared in the previous step, 19.0 mg, 0.0330 mmol) in 1 mL of 2:1TFA/DCM was stirred at RT for 4 h. Removal of the solvent under reducedpressure followed by flash chromatography of the residue on silica gel(10-20% EtOAc/DCM) gave 13.2 mg (90%) of the title compound as a whitesolid: ¹H-NMR (CDCl₃; 400 MHz): δ 12.00 (s, 1H), 10.29 (s, 1H), 8.33 (d,1H, J=8.3 Hz), 7.76 (d, 1H, J=2.3 Hz), 7.12 (dd, 1H, J=8.3, 1.7 Hz),7.06 (d, 1H, J=1.7 Hz), 3.14-3.22 (m, 4H), 3.01 (d, 2H, J=12.0 Hz),2.68-2.83 (m, 3H), 2.38-2.53 (m, 2H), 2.23 (d, 2H, J=14.5 Hz), 1.50-1.85(m, 5H), 1.09 (d, 3H, J=5.8 Hz). Mass spectrum (ESI, m/z): Calcd. forC₂₂H₂₇N₅O₃S, 442.2 (M+H), found 442.2.

The following compounds have been prepared according to the examples asindicated:

Mass Spectrum Mass Spectrum Proc. Example Structure Calcd [M + H]⁺ Found[M + H]+ Formula of Ex 48

479.3 479.2 C₂₆H₃₄N₆O₃ 42 4-[4-[(4-Cyano-1H-pyrrole-2-carbonyl)-amino]-3-(4-methyl-piperidin-1-yl)-phenyl]- piperidine-1-carboxylic acid(2-hydroxy-ethyl)-amide 49

505.3 505.2 C₂₆H₃₆N₆O₃ 42 4-Cyano-1H-pyrrole-2-carboxylic acid{2-(4-methyl-piperidin-1-yl)-4-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-phenyl}-amide 50

507.3 507.1 C₂₈H₃₈N₆O₃ 42 4-[4-[(4-Cyano-1H-pyrrole-2-carbonyl)-amino]-3-(4-methyl-piperidin-1-yl)-phenyl]- piperidine-1-carboxylic acid2-dimethylamino-ethyl ester 51

512.2 512.2 C₂₆H₃₃N₅O₄S 45 4-Cyano-1H-pyrrole-2-carboxylic acid[4-[1-(2-methanesulfonyl-acetyl)-piperidin-4-yl]-2-(4-methyl-piperidin-1-yl)-phenyl]-amide 52

441.2 441.1 C₂₃H₂₈N₄O₃S 47 steps a-f 4-Cyano-1H-pyrrole-2-carboxylicacid [4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide

Example 53 4-Cyano-1H-pyrrole-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide

To 62 mg (0.44 mmol) of 4-cyano-1H-pyrrole-2-carboxylic acid (asprepared in Example 2) in dichloromethane (20 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (107mg, 0.560 mmol), hydroxybenzotriazole (HOBt) (65 mg, 0.48 mmol), and4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenylamine (as prepared inExample 5, step (b), 100 mg, 0.370 mmol) and the mixture stirred for 24h at RT. The mixture was poured into satd aq sodium bicarbonate (50 mL)and extracted with dichloromethane (2×20 mL). The organic layers werewashed with brine (20 mL), dried over Na₂SO₄ and the solvent was removedin vacuo. Purification of the resulting residue by silica gelpreparative TLC eluting with 10% methanol in dichloromethane yielded 63mg (44%) of the title compound as a tan solid. ¹H-NMR (400 MHz, CDCl₃):δ 11.09 (br s, 1H), 9.11 (s, 1H), 8.25 (d, 1H, J=8.9 Hz), 7.45 (d, 1H,J=1.3 Hz), 6.88 (d, 1H, J=1.1 Hz), 6.81 (d, 1H, J=2.6 Hz), 6.75 (dd, 1H,J=8.9, 2.6), 3.21 (m, 4H), 2.84 (m, 4H), 2.62 (m, 4H), 2.38 (s, 3H),1.78 (m, 5H). LC-MS (ESI, m/z): Calcd. for C₂₂H₂₉N₆O, 393.2 (M+H);found: 393.2.

Example 54 4-Cyano-1H-pyrrole-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide

The procedure of Example 53 was followed using4-cyano-1H-pyrrole-2-carboxylic acid (as prepared in Example 2, 56 mg,0.22 mmol) and4-(4-methyl-piperazin-1-yl)-2-(4-methyl-piperidin-1-yl)-phenylamine (asprepared in Example 13, step (a), 61 mg 0.21 mmol). Purification of theresulting residue by silica gel preparative TLC eluting with 10%methanol in dichloromethane yielded 47 mg (55%) of the title compound asan off-white solid. ¹H-NMR (400 MHz, CDCl₃): δ 9.60 (br s, 1H), 8.30 (d,1H, J=8.9), 7.24 (d, 1H, J=3.7 Hz), 7.21 (d, 1H, J=3.7 Hz), 6.79 (d, 1H,J=2.7 Hz), 6.73 (dd, 1H, J=8.9, 2.7 Hz), 3.20 (m, 4H), 3.00-2.97 (m,2H), 2.76-2.70 (m, 2H), 2.59 (m, 4H), 2.37 (s, 3H), 1.85-1.82 (m, 2H),1.56-1.46 (m, 2H), 1.07 (d, 3H, J=6.2 Hz). LC-MS (ESI, m/z): Calcd. forC₂₃H₃₁N₆O, 407.3 (M+H); found: 407.2.

Example 55 5-Cyano-furan-2-carboxylic acid[4-methyl-6′-(4-methyl-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-amide

a) 6′-Chloro-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

A flask was charged with 2,6-dichloro-3-nitropyridine (1.00 g, 5.00mmol), absolute ethanol (25 mL), and 4-methylpiperidine (0.65 mL, 5.5mmol) and stirred 15 h at RT. The solvents were removed in vacuo andpurification of the resulting residue by silica gel preparative TLCeluting with 10% ethyl acetate in hexane yielded 577 mg (45%) of thetitle compound as a yellow glass. LC-MS (ESI, m/z): Calcd. forC₁₁H₁₅ClN₃O₂, 256.1/258.1 (M+H); found: 256.1/258.1.

b)4-Methyl-6′-(4-methyl-piperazin-1-yl)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

A flask was charged with6′-chloro-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (210mg, 0.820 mmol) (as prepared in the previous step), and1-methylpiperazine (182 μL, 1.65 mmol) and the mixture was stirred at145° C. for 3 h. Purification of the resulting residue by silica gelpreparative TLC eluting with 10% methanol in dichloromethane yielded 202mg (77%) of the title compound as yellow glass. ¹H-NMR (400 MHz, CDCl₃):δ 8.19 (d, 1H, J=9.2 Hz), 6.03 (d, 1H, J=9.2 Hz), 3.82 (m, 2H), 3.70 (m,4H), 2.98 (m, 2H), 2.48 (m, 2H), 2.34 (s, 3H), 1.71-1.60 (m, 3), 1.35(m, 2H), 0.97 (d, 3H, J=6.3 Hz). LC-MS (ESI, m/z): Calcd. forC₁₆H₂₆N₅O₂, 320.2 (M+H); found: 320.1.

c)4-Methyl-6′-(4-methyl-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine

A flask was charged with4-methyl-6′-(4-methyl-piperazin-1-yl)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl(101 mg, 0.320 mmol), methanol (10 mL), ammonium chloride (171 mg, 3.20mmol), and iron powder (88 mg, 1.6 mmol) and refluxed for 10 h.Additional amounts of ammonium chloride (171 mg, 3.20 mmol) and ironpowder (88 mg, 1.6 mmol) were added after 2.5 h and 6 h during thereflux operation. The cooled mixture was poured into satd aq sodiumbicarbonate (100 mL), extracted with dichloromethane (4×20 mL), and theorganic layers were dried over Na₂SO₄. The solvents were removed invacuo to yield 80 mg (87%) of the title compound as a green glass.¹H-NMR (400 MHz, CDCl₃): δ 6.89 (d, 1H, J=8.3), 6.21 (d, 1H, J=8.3 Hz),3.45-3.36 (m, 8H), 2.71 (m, 2H), 2.54 (m, 4H), 2.34 (s, 3H), 1.74-1.71(m, 2H), 1.52 (m, 1H), 1.31 (m, 2H), 0.98 (d, 3H, J=6.5 Hz). LC-MS (ESI,m/z): Calcd. for C₁₆H₂₈N₅, 290.2 (M+H); found: 290.2.

d) 5-Cyano-furan-2-carboxylic acid[4-methyl-6′-(4-methyl-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-3′-yl]-amide

The title compound was prepared according to the procedure from Example4, step (c) using 2-cyano-5-furancarboxylic acid (as prepared inExample 1) and4-methyl-6′-(4-methyl-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine(as prepared in the previous step). Purification of the resultingresidue by silica gel preparative TLC eluting with 10% methanol indichloromethane afforded the title compound in 50% as a yellow glass.¹H-NMR (400 MHz, CDCl₃): δ 8.76 (br s, 1H), 8.410 (d, 1H, J=8.8 Hz),7.24 (d, 1H, J=3.7 Hz), 7.21 (d, 1H, J=3.7 Hz), 6.37 (d, 1H, J=8.8 Hz),3.53 (m, 4H), 3.21-3.18 (m, 2H), 2.85 (m, 2H), 2.52 (m, 4H), 2.34 (s,3H), 1.82-1.79 (m, 2H), 1.57 (m, 1H), 1.47-1.37 (m, 2H) 1.05 (d, 3H,J=6.5 Hz). NOE 1H-NMR experiments confirmed the correct regiochemicalassignment. LC-MS (ESI, m/z): Calcd. for C₂₂H₂₉N₆O₂, 409.2 (M+H); found:409.2.

Example 56 4-Cyano-1H-pyrrole-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-piperazin-1-yl-phenyl]-amidebis(trifluoroacetic acid salt)

a)4-[4-[(4-Cyano-1H-pyrrole-2-carbonyl)-amino]-3-(4-methyl-piperidin-1-yl)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

Prepared according to the procedure from Example 53 using4-cyano-1H-pyrrole-2-carboxylic acid (as prepared in Example 2) and4-[4-amino-3-(4-methyl-piperidin-1-yl)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester as prepared in Example 15, step (c). Purificationof the resulting residue by silica gel preparative TLC eluting with 20%ethyl acetate in dichloromethane afforded the title compound in 47% asan off-white solid. ¹H-NMR (400 MHz, CDCl₃): δ 11.13 (br s, 1H), 9.05(s, 1H), 8.29 (d, 1H, J=8.9), 7.48 (dd, 1H, J=3.0, 1.3 Hz), 6.88 (s,1H), 6.84 (d, 1H, J=2.6 Hz), 6.76 (dd, 1H, J=8.9, 2.2 Hz), 3.62 (m, 4H),3.13 (m, 4H), 3.01-2.98 (m, 2H), 2.73 (m, 2H), 1.88-1.85 (m, 2H),1.61-1.56 (m, 2H), 1.51 (s, 9H), 1.50-1.37 (m, 2H), 1.10 (d, 3H, J=6.5Hz). LC-MS (ESI, m/z): Calcd. for C₂₇H₃₇N₆O₃, 493.3 (M+H); found: 493.1.

b) 4-Cyano-1H-pyrrole-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-piperazin-1-yl-phenyl]-amidebis(trifluoroacetic acid salt)

To4-[4-[(4-cyano-1H-pyrrole-2-carbonyl)-amino]-3-(4-methyl-piperidin-1-yl)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (80 mg, 0.16 mmol, as prepared in the previousstep) in dichloromethane (2 mL) was added TFA (2 mL) and water (50 μL)and the mixture was stirred for 2 h at RT. The solvents were removed invacuo and the resulting residue was purified by silica gel preparativeTLC eluting with 10% methanol in dichloromethane yielding 92 mg (92%) ofthe title compound as an off-white solid. ¹H-NMR (400 MHz, CDCl₃): δ12.67 (br s, 1H), 9.04 (s, 1H), 8.72 (br s, 2H), 7.78 (d, 1H, J=1.5 Hz),7.63 (d, 1H, J=8.4 Hz), 7.31 (s, 1H), 6.76 (d, 1H, J=2.6 Hz), 6.69 (dd,1H, J=8.8, 2.6 Hz), 3.46-3.17 (m, 8H), 3.00-2.97 (m, 2H), 2.62 (m, 2H),1.69-1.67 (m, 2H), 1.47 (m, 1H), 1.35 (m, 2H), 0.97 (d, 3H, J=6.3 Hz).LC-MS (ESI, m/z): Calcd. for C₂₂H₂₉N₆O, 393.2 (M+H); found: 393.1.

Example 57 4-Cyano-1H-pyrrole-2-carboxylic acid[4-(4-acetyl-piperazin-1-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide

To 4-cyano-1H-pyrrole-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-piperazin-1-yl-phenyl]-amidetrifluoroacetic acid salt (as prepared in Example 56, step (b)) (30 mg,0.048 mmol) in dichloromethane (5 mL) was added acetic anhydride (7.0μL, 0.072 mmol) and DIEA (31 μL, 0.18 mmol) and the mixture was stirredfor 5 h at RT. The mixture was poured into saturated aq sodiumbicarbonate (5 mL), extracted with dichloromethane (5 mL), and theorganic layer was dried (Na₂SO₄). The solvents were removed in vacuo andthe resulting residue was purified by silica gel preparative TLC elutingwith 10% methanol in dichloromethane to yield 4.9 mg (23%) of the titlecompound as an off-white solid. ¹H-NMR (400 MHz, CDCl₃): δ 10.57 (br s,1H), 8.99 (s, 1H), 8.27 (d, 1H, J=8.8 Hz), 7.45 (dd, 1H, J=3.1, 1.3 Hz),6.851 (s, 1H), 6.81 (d, 1H, J=3.5 Hz), 6.73 (dd, 1H, J=8.9, 2.6 Hz),3.79 (m, 2H), 3.64 (m, 2H), 3.17-2.96 (m, 4H), 2.74 (m, 2H), 2.70 (m,2H), 2.15 (s, 3H), 1.87-1.84 (m, 2H), 1.58 (m, 1H), 1.44-1.34 (m, 2H),1.08 (d, 3H, J=6.5 Hz). LC-MS (ESI, m/z): Calcd. for C₂₄H₃₁N₆O₂, 435.2(M+H); found: 435.1.

Example 58 4-Cyano-1H-pyrrole-2-carboxylic acid[4-methyl-6′-(4-methyl-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-amide

A flask was charged with 4-cyano-pyrrole-2-carboxylic acid (as preparedin Example 2, 200 mg, 1.43 mmol), dichloromethane (30 ml), DMF (150 μL),and oxalyl chloride (275 μL, 1.60 mmol) and the mixture was stirred for20 min at RT. Toluene (10 mL) was then added and the solvents wereremoved in vacuo. To the resulting acid chloride, dichloromethane (30mL), DIEA (750 μL, 4.30 mmol), and4-methyl-6′-(4-methyl-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine(as prepared in Example 55, step (c), 385 mg, 1.33 mmol) were added andthe mixture was stirred at RT for 4 days. The mixture was poured intosaturated aq sodium bicarbonate (100 mL), and extracted withdichloromethane (2×25 mL) and the solvents were removed in vacuo.Purification of the resulting residue by silica gel preparative TLCeluting with 10% methanol in dichloromethane, then repurification byalumina preparative TLC eluting withdichloromethane-acetonitrile-methanol (7:2.5:0.5) yielded 38 mg (7%) ofthe title compound as a green solid. ¹H-NMR (400 MHz, CDCl₃): δ 11.32(br s, 1H), 8.33 (d, 1H, J=8.8 Hz), 7.44 (s, 1H), 6.87 (s, 1H), 6.39 (d,1H, J=8.8 Hz), 3.54 (m, 4H), 3.18-3.15 (m, 2H), 2.84 (m, 2H), 2.56 (m,4H), 2.38 (s, 3H), 1.82-1.79 (m, 2H), 1.56 (m, 1H), 1.40-1.33 (m, 2H)1.06 (d, 3H, J=6.5 Hz). LC-MS (ESI, m/z): Calcd. for C₂₂H₃₀N₇O, 408.2(M+H); found: 408.2.

Example 59 5-Cyano-furan-2-carboxylic acid[2-(4-methyl-piperazin-1-yl)-4-(4-methyl-piperidin-1-yl)-pyrimidin-5-yl]-amidetrifluoroacetic acid salt

a) 2-Chloro-4-(4-methyl-piperidin-1-yl)-5-nitro-pyrimidine

To a solution of 2,4-dichloro-5-nitropyrimidine (194 mg, 1.00 mmol) inTHF (10 mL) at −40° C., 4-methylpiperidine (118 μL, 1.00 mmol) was addeddropwise. The resulting mixture was stirred at −40° C. for 3 h and thesolvent was removed in vacuo. The resulting yellow residue waschromatographed on silica (5-20% EtOAc:hexane) to obtain the titlecompound (103 mg, 40%). ¹H-NMR (CDCl₃; 400 MHz): δ 8.69 (s, 1H), 4.24(br m, 2H), 3.10 (m, 2H, J=12.9, 2.7 Hz), 1.82-1.71 (m, 3H), 1.36-1.25(m, 2H), 1.01 (d, 3H, J=4.8 Hz).

b)2-(4-Methyl-piperazin-1-yl)-4-(4-methyl-piperidin-1-yl)5-nitro-pyrimidine

To a solution of 2-chloro-4-(4-methyl-piperidin-1-yl)-5-nitro-pyrimidine(as prepared in the previous step) (257 mg, 1.00 mmol) in DMF (10 mL)was added 1-methyl piperazine (110 μL, 1.00 mmol). The resulting mixturewas heated at 80° C. for 48 h. The reaction mixture was allowed to coolto room temperature and partitioned between water/EtOAc. The EtOAc layerwas separated, dried (Na₂SO₄) and concentrated in vacuo. The residueobtained was purified on silica (0-10% MeOH:EtOAc) to obtain the titlecompound (192 mg, 63%). ¹H-NMR (CDCl₃; 400 MHz): δ 8.76 (s, 1H), 3.90(br m, 6H), 2.96 (m, 2H), 2.40 (m, 4H), 2.32 (s, 3H), 1.82-1.6 (m, 3H),1.2-1.3 (m, 2H), 1.02 (d, 3H, J=6.5 Hz).

c. 5-Cyano-furan-2-carboxylicacid[2-(4-methyl-piperazin-1-yl)-4-(4-methyl-piperidin-1-yl)-pyrimidin-5-yl]-amide trifluoroacetic acid salt

2-(4-Methyl-piperazin-1-yl)-4-(4-methyl-piperidin-1-yl)-5-nitro-pyrimidine(as prepared in the previous step) (320 mg, 1.00 mmol) was converted tocorresponding amine according to the procedure in Example 55, step (c)and coupled with 5-cyano-furan-2-carbonyl chloride as prepared inExample 4, step (c) (obtained from 137 mg, 1.00 mmol of5-cyano-furan-2-carboxylic acid as prepared in Example 1) in DMF (2 mL)at 0° C. The product was isolated by reversed-phase chromatography onC-18 column (eluting with 20-80% CH₃CN/1% TFA:H₂O) to obtain the titlecompound (28 mg, 6%). ¹H-NMR (CDCl₃; 400 MHz): δ 9.79 (s, 1H), 8.05 (s,1H), 7.31 (d, 1H, J=3.7 Hz), 7.18 (d, 1H, J=3.7 Hz), 6.08 (br m, 3H),4.61 (m, 3H), 3.69 (br m, 3H),), 3.07 (m, 3H), 2.92 (s, 3H), 1.92-1.80(m, 3H), 1.15-1.3 (m, 2H), 0.97 (d, 3H, J=6.3 Hz). LC-MS (ESI, m/z):Calcd. for C₂₁H₂₇N₇O₂, 410.2 (M+H), found 410.2.

Example 60 5-Cyano-furan-2-carboxylicacid[4-methyl-5′-(4-methyl-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-yl]-amide

a) 3,5-dicholoro-2-nitro pyridine

2-Amino-3,5-dichloropyridine (193 mg, 1.00 mmol) was dissolved in concH₂SO₄ (5 mL) and K₂S₂O₈ (1.3 g, 5.0 mmol) was added portionwise. Theresulting mixture was stirred at RT overnight and poured onto crushedice and neutralized with satd aq NaHCO₃. The product was extracted withCH₂Cl₂ (3×20 mL), dried (Na₂SO₄) and concentrated in vacuo to obtain thetitle compound (123 mg, 63.7%). ¹H-NMR (CDCl₃; 400 MHz): δ 8.40 (d, 1H,J=2.1 Hz), 8.05 (d, 1H, J=2.1 Hz).

b) 5′-Chloro-4-methyl-2′-nitro-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl

A mixture of 3,5-dichloro-2-nitropyridine (193 mg, 1.00 mmol),4-methylpiperidine (118 μL, 1.00 mmol) and K₂CO₃ (138 mg, 1.00 mmol) intoluene (10 mL) was heated at 50° C. for 3 h. Toluene was removed invacuo and the residue obtained was purified on silica (2% EtOAc/hexane)to obtain the title compound (153 mg, 60%). ¹H-NMR (CDCl₃; 400 MHz): δ7.95 (s, 1H, J=2.5 Hz), 7.58 (s, 1H, J=2.5 Hz), 3.30 (m, 2H), 2.95 (m,2H), 1.87 (m; 2H), 1.65 (m, 1H), 1.35 (m, 2H), 1.0 (d, 3H, J=6.3 Hz).

c)4-Methy-5′-(4-methyl-piperazin-1-yl)-2′-nitro-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl

To a solution of5′-chloro-4-methyl-2′-nitro-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl (asprepared in the previous step) (255 mg, 1.00 mmol) in DMF (10 mL) wasadded 1-methyl piperazine (110 μL, 1.00 mmol). The resulting mixture washeated at 125° C. overnight. The reaction mixture was allowed to cool toroom temperature and partitioned between water and EtOAc. The EtOAclayer was separated, dried (Na₂SO₄) and concentrated in vacuo. Theresidue obtained was purified on silica (10-50% EtOAc:hexane) to obtainthe title compound (204 mg, 64%). ¹H-NMR (CDCl₃; 400 MHz): δ 7.67 (d,1H, J=2.52 Hz), 6.69 (d, 1H, J=2.52 Hz), 3.39 (m, 4H), 3.29 (m, 2H),2.75 (m, 2H), 2.56 (m, 4H), 2.35 (s, 3H), 1.71 (m, 2H), 1.6-1.5 (m, 3H),0.99 (d, 3H, J=6.3 Hz).

d) 5-Cyano-furan-2-carboxylicacid[4-methyl-5′-(4-methyl-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-yl]-amide

4-Methy-5′-(4-methyl-piperazin-1-yl)-2′-nitro-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl(as prepared in the previous step) (319 mg, 1.00 mmol) was converted tocorresponding amine according to the procedure in Example 55, step (c)and coupled with 5-cyano-furan-2-carbonyl chloride as prepared inExample 4, step (c) (obtained from 137 mg, 1.00 mmol of5-cyano-furan-2-carboxylic acid as prepared in Example 1) in DMF (2 mL)at 0° C. The product was isolated by flash chromatography on silica (20%EtOAc/hexane-10% MeOH/EtOAc) to obtain the title compound (16 mg, 4%).¹H-NMR (CDCl₃; 400 MHz): δ 9.35 (br s, 1H), 7.95 (br s, 1H), 7.33 (d,1H, J=3.5 Hz), 7.22 (d, 1H), J=3.5 Hz), 7.06 (br s, 1H), 3.21 (m, 4H),3.06 (m, 2H), 2.71 (m, 2H), 2.58 (m, 4H), 2.37 (s, 3H), 1.84 (m, 2H),1.7-1.5 (m, 3H), 1.07 (d, 3H, J=6.3 Hz). LC-MS (ESI, m/z); Calcd. forC₂₂H₂₈N₆O₂, 409.2 (M+H), found 409.2.

Example 61 5-Cyano-furan-2-carboxylicacid[4-methyl-6′-(4-methyl-2-oxo-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-yl]-amide

a) 6′-Bromo-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

A mixture of 2,6-dibromo-3-nitropyridine (Duffy, J., et al, J. Org.Chem. 56, (9), 3006, (1991)) (282 mg, 1.00 mmol), 4-methylpiperidine(118 μL, 1.00 mmol) and K₂CO₃ (138 mg, 1.00 mmol) in toluene (10 mL) washeated at 50° C. for 3 h. Toluene was removed in vacuo and the residueobtained was purified on silica (2% EtOAc/hexane) to obtain the titlecompound (197 mg, 66%). ¹H-NMR (CDCl₃; 400 MHz): δ 8.32 (d, 1H J=8.2Hz), 7.94 (d, 1H J=8.2 Hz), 3.82 (m, 2H), 3.04 (m, 2H), 1.85 (m, 3H),1.3 (m, 2H), 0.99 (d, 3H, J=6.4 Hz).

b)4-Methyl-1-(4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-2-one

To a solution of6′-bromo-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (asprepared in the previous step) (300 mg, 1.00 mmol) in toluene (5 mL) wasadded 3-oxo-piprazine-1-carboxylic acid benzyl ester (351 mg, 1.50mmol), K₃PO₄ (424 mg, 2.00 mmol) and CuI (38 mg, 0.20 mmol) followed byN,N′-dimethylethylenediamine (20 μL, 0.18 mmol) under Ar. The resultingmixture was heated at reflux overnight. The reaction mixture was allowedto cool to room temperature and filtered through a thin pad of Celite.The filtrate was concentrated in vacuo and the residue obtained waspurified by chromatography on silica (20% EtOAc:hexane) to obtain4-(4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-3-oxo-piperazine-1-carboxylicacid benzyl ester (258 mg, 57%). This compound (453 mg, 1.00 mmol) wasdissolved in 30% HBr/HOAc (1 mL). The resulting mixture was stirred atroom temperature overnight and Et₂O (20 mL) was added dropwise. Theresulting mixture was stirred for another hour, the precipitatedhydrobromide was collected by suction filtration, washed with Et₂O (3×20mL), dried in vacuo for 1 h and used directly in next step.

The above hydrobromide (48 mg, 0.10 mmol) was added to 37% aq HCHO (ca.0.05 mL, 0.05 mmol) followed by NaBH(OAc)₃ (106 mg, 0.050 mmol). Theresulting mixture was stirred at room temperature for 30 min and theproduct was extracted with CH₂Cl₂ (3×10 mL). The CH₂Cl₂ layers werecombined, dried (Na₂SO₄) and concentrated in vacuo. The residue obtainedwas purified on silica (10-50% EtOAc:hexane) to obtain the titlecompound (27 mg, 81%). ¹H-NMR (CDCl₃; 400 MHz): δ 8.21 (d, 1H, J=8.9Hz), 7.58 (d, 1H, J=8.9 Hz), 3.98 (m, 2H), 3.75 (m, 2H), 3.31 (s, 2H),2.96 (m, 2H), 2.72 (m, 2H), 2.39 (s, 3H), 1.9-1.65 (m, 3H), 1.25 (m,2H), 0.99 (d, 3H, J=6.42 Hz).

c) 5-Cyano-furan-2-carboxylicacid[4-methyl-6′-(4-methyl-2-oxo-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-amide

4-Methyl-1-(4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-2-one(as prepared in the previous step) (99 mg, 0.29 mmol) was converted tocorresponding amine according to the procedure in Example 55, step (c)and coupled with 5-cyano-furan-2-carbonyl chloride as prepared inExample 4, step (c) (obtained from 68.5 mg, 0.500 mmol of5-cyano-furan-2-carboxylic acid as prepared in Example 1) in CH₂Cl₂ (2mL) at 0° C. The product was isolated flash chromatography on silica(20% EtOAc/hexane-10% MeOH/EtOAc) to give the title compound (53 mg,43%). ¹H-NMR (CDCl₃; 400 MHz): δ 8.98 (br s, 1H), 8.61 (d, 1H, J=8.7Hz), 7.71 (d, 1H, J=8.7 Hz), 7.28 (d, 1H, J=3.7 Hz), 7.22 (d, 1H, J=3.7Hz), 3.99 (m, 2H), 3.28 (s, 2H), 3.16 (m, 2H), 2.87-2.77 (m, 4H), 2.38(s, 3H), 1.83 (m, 2H), 1.62 (m, 1H), 1.44 (m, 2H), 1.04 (d, 3H, J=6.3Hz). LC-MS (ESI, m/z): Calcd. for C₂₂H₂₆N₆O₃, 423.2 (M+H), found 423.1

Example 62 5-Cyano-furan-2-carboxylicacid[4-methyl-6′-(4-methyl-3-oxo-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-amide

a) 4-Methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester

To a solution of 3-oxo-piperazine-1-carboxylic acid benzyl ester (2.00g, 8.54 mmol) in DMF (30 mL) was added KOtBu (1.54 g, 13.7 mmol) underAr. The resulting solution was stirred at room temperature for 15 minand cooled to 0° C. MeI (0.85 mL, 14 mmol) was then added dropwise. Thereaction mixture was allowed to warm to room temperature and stirred for3 h. DMF was removed in vacuo and the residue was chromatographed onsilica (5-50% EtOAc:hexane) to obtain the title compound (1.40 g, 66%).¹H-NMR (CDCl₃; 400 MHz): δ 7.32 (m, 5H), 5.13 (s, 2H), 4.13 (s, 2H),3.70 (m, 2H), 3.34 (m, 2H), 2.97 (s, 3H)

b)1-Methyl-4-(4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-2-one

4-Methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (as prepared inthe previous step) (124 mg, 0.50 mmol) was dissolved in 30% HBr/HOAc(0.5 mL). The resulting mixture was stirred at room temperatureovernight and Et₂O (20 mL) was added drop wise. The resulting mixturewas stirred for another hour and the precipitate formed was collected bysuction filtration, washed with Et₂O (3×20 mL), dried in vacuo for 1 hand directly used in next step.

To a solution of6′-chloro-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (asprepared in Example 55, step (a)) (510 mg, 2.00 mmol) in DMF (10 mL) wasadded 1-methyl piperazinone hydrobromide (390 mg, 2.00 mmol) and K₂CO₃(691 mg, 5.00 mmol). The resulting mixture was heated at 100° C.overnight. DMF was removed in vacuo and the residue obtained waspurified on silica (20-100% EtOAc:hexane) to obtain the title compound(540 mg, 81%). ¹H-NMR (CDCl₃; 400 MHz): δ 8.15 (d, 1H, J=9.1 Hz), 5.94(d, 1H, J=9.1 Hz), 4.22 (s, 2H), 3.88 (m, 2H), 3.76 (m, 2H), 3.46 (m,2H), 3.01-2.92 (m, 5H), 1.68 (m, 3H), 1.25 (m, 2H), 0.93 (d, 3H, J=6.3Hz).

c) 5-Cyano-furan-2-carboxylicacid[4-methyl-6′-(4-methyl-3-oxo-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-amide

1-Methyl-4-(4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-2-one(as prepared in previous step) (166 mg, 0.50 mmol) was converted to thecorresponding amine according to the procedure in Example 55, step (c)and coupled with 5-cyano-furan-2-carbonyl chloride as prepared inExample 4, step (c) (obtained from 137 mg, 1.00 mmol of5-cyano-furan-2-carboxylic acid as prepared in Example 1) in CH₂Cl₂ (2mL) at 0° C. The product was isolated by flash chromatography on silica(20% EtOAc/hexane-10% MeOH/EtOAc) to obtain the title compound (108 mg,51%). ¹H-NMR (CDCl₃; 400 MHz): δ 8.73 (br s, 1H), 8.44 (d, 1H, J=8.7Hz), 7.24 (d, 1H, J=3.7 Hz), 7.22 (d, 1H, J=3.7 Hz), 6.32 (d, 1H, J=8.7Hz), 4.16 (m, 2H), 3.84 (m, 2H), 3.46 (m, 2H), 3.20 (m, 2H), 3.04 (s,3H), 2.84 (m, 2H), 1.8 (m, 2H), 1.4 (m, 1H), 1.32 (m, 2H), 1.04 (d, 3H,J=6.3 Hz). LC-MS (ESI, m/z): Calcd. for C₂₂H₂₆N₆O₃, 423.2 (M+H), found423.1

Example 63 5-Cyano-furan-2-carboxylic acid[4,1″-dimethy-3,4,5,6,1″,2″,3″,4″,5″,6″-decahydro-2H-{1,2′,6′,4″]terpyridin-3′-yl)-amide

a)4,1″-Dimethyl-3′-nitro-3,4,5,6,1″,2″,3″,6″-octahydro-2H-[1,2′,6′,4″]terpyridine

5′-Chloro-4-methyl-2′-nitro-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl (asdescribed in Example 55, step (a)) (159 mg, 0.790 mmol), K₂CO₃ (310 mg,2.25 mmol) and4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (Eastwood, P. R., Tetrahedron Letters, 41, (19),(2000)) (231 mg, 0.750 mmol) in dioxane (5 mL) were heated at 80° C.overnight under Ar. The reaction mixture was allowed to cool to RT,concentrated and the resulting residue was chromatographed on silica(10% EtOAc/hexane) to obtain the coupled compound (139 mg, 44%). Thiscompound (139 mg, 0.340 mmol) was dissolved in 1:1 mixture of TFA/CH₂Cl₂(5 mL) and the resulting mixture was stirred at RT for 1 hr. Thereaction mixture was concentrated and the resulting residue was dried invacuo for 2 h and dissolved in 37% aq. HCHO (1 mL). Na(OAc)₃BH (464 mg,2.10 mmol) was then added and the resulting mixture was stirred for 1 h.The reaction mixture was diluted with std aq NaHCO₃ and the product wasextracted with CH₂Cl₂ (3×10 mL). The organic layers were combined, dried(Na₂SO₄) and concentrated. The product was isolated by flashchromatography on silica (20% EtOAc/hexane) to obtain the title compound(66 mg, 60%). LC-MS (ESI, m/z): Calcd. for C₁₇H₂₄N₄O₂, 317.2 (M+H),found 317.0

b)4,1″-Dimethyl-3,4,5,6,1″,2″,3″,4″,5″,6″-decahydro-2H-[1,2′,6′,4″]terpyridine-3′-ylamine

4,1″-Dimethyl-3′-nitro-3,4,5,6,1″,2″,3″,6″-octahydro-2H-[1,2′,6′,4″]terpyridine(as prepared in the previous step) (60 mg, 0.20 mmol) was dissolved inMeOH (10 mL) and hydrogenated over 10% Pd/C (30 mg) under H₂ balloonpressure for 2 h. The reaction mixture was filtered through a thin padof Celite. The filtrate was concentrated and the residue obtained waspurified on silica with 5% NH₃/MeOH to obtain the title compound (41 mg,75%). LC-MS (ESI, m/z): Calcd. for C₁₇H₂₈N₄, 289.23 (M+H), found 289.3.

c) 5-Cyano-furan-2-carboxylicacid[4,1″-dimethy-3,4,5,6,1″,2″,3″,4″,5″,6″decahydro2H-{1,2′,6′,4″]terpyridin-3′-yl)-amide

4,1″-Dimethyl-3,4,5,6,1″,2″,3″,4″,5″,6″-decahydro-2H-[1,2′,6′,4″]terpyridine-3′-ylamineas prepared in the previous step (41 mg, 0.12 mmol) was coupled with5-cyano-furan-2-carbonyl chloride as prepared in Example 4, step (c)(obtained from 69 mg, 0.50 mmol of 5-cyano-furan-2-carboxylic acid asprepared in Example 1) in CH₂Cl₂ (2 mL) at 0° C. The product wasisolated by flash chromatography on silica (20% EtOAc/hexane-10%MeOH/EtOAc) to obtain the title compound (20 mg, 35%). ¹H-NMR (CDCl₃;400 MHz): δ 9.12 (br s, 1H), 8.52 (d, 1H, J=8.7 Hz), 7.29 (d, 1H, J=3.7Hz), 7.24 (d, 1H, J=3.7 Hz), 6.92 (d, 1H, J=8.7 Hz), 3.20 (m, 2H), 2.9(m, 4H), 2.6 (m, 1H), 2.34 (s, 3H), 2.05 (m, 2H), 1.86 (m, 6H), 1.7 (m,1H), 1.5 (m, 2H), 1.04 (d, 3H, J=6.3 Hz). LC-MS (ESI, m/z): Calcd. forC₂₃H₂₉N₅O₂, 408.2 (M+H), found 408.2.

Example 64 5-Cyano-furan-2-carboxylicacid[4-[4-methyl-pierazin-1-yl)-2-morpholin-4-yl-phenyl]-amide

a) 4-[5-(4-methyl-piperazin-1 yl)-2-nitro-phenyl)-morpholine

To a mixture of 4-chloro-2-fluoronitrobenzene (175 mg, 1.00 mmol) andK₂CO₃ (139 mg, 1.00 mmol) in toluene (2 mL), morpholine (87 μL, 1.0mmol) was added at 0° C. The resulting mixture was allowed to warm to RTand stirred overnight. The reaction mixture was concentrated and theproduct was isolated by flash chromatography on silica (20%EtOAc/hexane) to obtain 4-(5-Chloro-2-nitro-phenyl)-morpholine (205 mg,67%). This compound (243 mg, 1.00 mmol) was dissolved in1-methylpiperazine (1 mL) and the resulting mixture was heated at 130°C. overnight. The reaction mixture was diluted with water and theproduct was extracted with DCM (3×10 mL). The DCM layers were combined,dried (Na₂SO₄) and concentrated to obtain the title compound (177 mg,58%). ¹H-NMR (CDCl₃; 400 MHz): δ 8.04 (d, 1H, J=9.4 Hz), 6.46 (dd, 1H,J=9.4, 2.6 Hz), 6.31 (d, 1H, =2.6 Hz), 3.89 (m, 4H), 3.40 (m, 4H), 3.07(m, 4H), 2.50 (m, 4H), 2.36 (s, 3H).

b) 5-Cyano-furan-2-carboxylicacid[4-[4-methyl-pierazin-1-yl)-2-morpholin-4-yl-phenyl]-amide

4-[5-(4-Methyl-piperazin-1-yl)-2-nitro-phenyl)-morpholine (as preparedin the previous step) (138 mg, 0.480 mmol) was converted tocorresponding amine according to the procedure in Example 55, step (c)and coupled with 5-cyano-furan-2-carbonyl chloride as prepared inExample 4, step (c) (obtained from 137 mg, 1.00 mmol of5-cyano-furan-2-carboxylic acid as prepared in Example 1) in CH₂Cl₂ (2mL) at 0° C. The product was isolated by flash chromatography on silica(25% EtOAc/hexane-10% MeOH/EtOAc) to obtain the title compound (87 mg,49%). ¹H-NMR (CDCl₃; 400 MHz): δ 9.40 (br s, 1H), 8.32 (d, 1H, J=8.7Hz), 7.26 (d, 1H, J=3.7 Hz), 7.22 (d, 1H, J=3.7 Hz), 6.80 (d, 1H, =2.6Hz), 6.78 (d, 1H, J=8.7 Hz), 3.93 (m, 4H), 3.20 (m, 4H), 2.92 (m, 4H),2.60 (m, 4H), 2.36 (s, 3H). LC-MS (ESI, m/z): Calcd. for C₂₁H₂₅N₅O₃,396.2 (M+H), found 396.2.

Example 65 5-Cyano-furan-2-carboxylic acid[4-methyl-6′-(tetrahydro-pyran-4-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-amide

a)6′-(3,6-Dihydro-2H-pyran-4-yl)-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

A mixture of6′-bromo-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (asprepared in Example 61, step (a)) (237 mg, 0.79 mmol), anhydrous K₂CO₃(311 mg, 2.25 mmol) and4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran(Murata, M., Synthesis, 778, (2000)) (157 mg, 0.750 mmol) in dioxane (5mL) was heated at 80° C. overnight under Ar. The reaction mixture wasallowed to cool to RT, concentrated and the resulting residue waspurified on silica (10% EtOAc/hexane) to obtain the expected coupledcompound (71 mg, 30%). ¹H-NMR (CDCl₃; 400 MHz): δ 8.15 (d, 1H, J=8.4Hz), 6.80 (m, 2H), 4.39 (m, 2H), 3.92 (t, 2H, J=5.4 Hz), 3.76 (m, 2H),3.04 (m, 2H), 2.62 (m, 2H), 1.67 (m, 3H), 1.33 (m, 2H), 0.99 (d, 3H,J=6.3 Hz).

b) 5-Cyano-furan-2-carboxylic acid[4-methyl-6′-(tetrahydro-pyran-4-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-amide

6′-(3,6-Dihydro-2H-pyran-4-yl)-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H[1,2′]bipyridinyl (as prepared in the previous step) (70 mg, 0.23 mmol)was dissolved in MeOH (10 mL) and hydrogenated over 10% Pd/C (30 mg)under H₂ balloon pressure for 2 h. The reaction mixture was filteredthrough a thin pad of Celite. The filtrate was concentrated and theresidue obtained was purified on silica 5% NH₃/MeOH to obtain thecorresponding aniline compound (46 mg, 72%).

The above aniline (138 mg, 0.500 mmol) was coupled with5-cyano-furan-2-carbonyl chloride as prepared in Example 4, step (c)(obtained from 137 mg, 1.00 mmol of 5-cyano-furan-2-carboxylic acid asprepared in the Example 1) in CH₂Cl₂ (2 mL) at 0° C. The product wasisolated by flash chromatography on silica (20% EtOAc/hexane-10%MeOH/EtOAc) to obtain the title compound (69 mg, 35%). ¹H-NMR (CDCl₃;400 MHz): δ 9.10 (br s, 1H), 8.52 (d, 1H, J=8.2 Hz), 7.28 (d, 1H, J=4.4Hz), 7.24 (d, 1H, J=4.4 Hz), 6.91 (d, 1H, J=8.2 Hz), 4.07 (m, 2H), 3.53(m, 2H), 3.15 (m, 2H), 2.80 (m, 3H), 1.85 (m, 6H), 1.65 (m, 1H), 1.45(m, 2H), 1.04 (d, 3H, J=6.3 Hz). LC-MS (ESI, m/z): Calcd. forC₂₂H₂₆N₄O₃, 395.2 (M+H), found 395.2.

Example 66 5-Cyano-1H-imidazole-2-carboxylic acid[4-methyl-6′-(tetrahydro-pyran-4-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-amide

6′-(3,6-Dihydro-2H-pyran-4-yl)-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H[1,2′]bipyridinyl (as prepared in Example 65, step (a)) (70 mg, 0.23mmol) was dissolved in MeOH (10 mL) and hydrogenated over 10% Pd/C (30mg) under H₂ balloon pressure for 2 hr. The reaction mixture wasfiltered through a thin pad of Celite. The filtrate was concentrated andthe residue obtained was purified on silica 5% NH₃/MeOH to obtain thecorresponding aniline compound (46 mg, 72%).

The above aniline (112 mg, 0.400 mmol) was coupled with5-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid potassium salt (as prepared in Example 3) as described in Example47, step (e). The product was isolated by flash chromatography on silica(20% EtOAc/hexane-10% MeOH/EtOAc) (97 mg, 45%). This compound (84 mg,0.15 mmol) was dissolved in 2:1 TFA/DCM (5 mL) and allowed to stir at RTfor 4 h. The reaction mixture was concentrated and the product waspartitioned between DCM and satd aq NaHCO₃. The DCM layer was separated,dried (Na₂SO₄) and concentrated to obtain the titled compound (55 mg,88%). ¹H-NMR (CDCl₃; 400 MHz): δ 12.63 (br s, 1H), 9.84 (br s, 1H), 8.46(d, 1H, J=8.2 Hz), 7.82 (s, 1H), 6.91 (d, 1H, J=8.2 Hz), 4.10 (m, 2H),3.61 (m, 2H), 3.23 (m, 2H), 2.92 (m, 3H), 1.98 (m, 7H), 1.35 (m, 2H),0.98 (d, 3H, J=6.3 Hz). LC-MS (ESI, m/z): Calcd. for C₂₁H₂₆N₆O₂, 395.2(M+H), found 395.4.

Example 67 5-Cyano-furan-2-carboxylic acid{4-methyl-6′-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl}-amide

a) 6′-Chloro-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

A solution of 2,6-dichloro-3-nitro-pyridine (1.47 g, 7.61 mmol) intoluene (40 mL) was treated with, solid K₂CO₃ (1.26 g, 9.13 mmol) and4-methyl-piperidine (0.90 mL, 7.6 mmol). The reaction was stirred atroom temperature for 1.5 h, additional toluene (10 mL) was added, andthe reaction was stirred an additional 5 h. The reaction was dilutedwith EtOAc and washed with water. The aqueous layer was furtherextracted with EtOAc. The combined organic layers were dried over MgSO₄and concentrated in vacuo to afford the title compound (2.00 g, 100%) asa waxy, bright yellow solid. ¹H-NMR (CDCl₃; 400 MHz): δ 8.06 (d, 1H,J=4.0 Hz), 7.61 (d, 1H, J=4.0 Hz), 3.83-3.75 (m, 2H), 3.08-2.97 (m, 2H),1.77-1.68 (m, 2H), 1.57 (br s, 1H), 1.37-1.23 (m, 2H), 0.98 (d, 3H,J=6.4 Hz). LC-MS (ESI, m/z): Calcd. for C₁₁H₁₄ClN₃O₂, 256.1 (M+H), found256.1.

b)4-(4-Methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazine-1-carboxylicacid benzyl ester

A solution of6′-chloro-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (asprepared in the previous step, 2.0 g, 7.8 mmol) in DMF (40 mL) wastreated with solid Na₂CO₃ (0.99 g, 9.4 mmol) and piperazine-1-carboxylicacid benzyl ester (1.5 mL, 7.8 mmol), then heated to 90° C. for 1 h andto 40° C. for 15 h. The reaction was concentrated to 20 mL volume,diluted with EtOAc, and washed well with water. The combined aqueouslayers were further extracted with EtOAc. The combined organic layerswere dried over MgSO₄ and concentrated in vacuo. Silica gelchromatography (25% EtOAc in hexane) afforded the title compound (3.2 g,94%) as a yellow solid. ¹H-NMR (CDCl₃; 400 MHz): δ 8.19 (d, 1H, J=9.2Hz), 7.39-7.31 (m, 5H), 6.01 (d, 1H, J=9.2 Hz), 5.16 (s, 2H), 3.84-3.76(m, 2H), 3.71-3.65 (m, 4H), 3.64-3.58 (m, 4H), 3.02-2.93 (m, 2H),1.74-1.65 (m, 2H), 1.66-1.60 (m, 1H), 1.38-1.26 (m, 2H), 0.97 (d, 3H,J=6.4 Hz). LC-MS (ESI, m/z): Calcd. for C₂₃H₂₉N₅O₄, 440.2 (M+H), found439.9.

c)4-Methyl-3′-nitro-6′-piperazin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyldihydrobromide

A solution of4-(4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazine-1-carboxylicacid benzyl ester (as prepared in the previous step, 3.2 g, 7.3 mmol) inHOAc (50 mL) was treated with 30% HBr in HOAc (7.3 mL, 1 mL/mmol benzylester) and heated to 60° C. for 1 h. The reaction was cooled to roomtemperature and allowed to stir for 5 h, after which time Et₂O was addedto the reaction while stirring. The bright yellow precipitate wasfiltered and washed with Et₂O to afford the title compound (2.6 g, 77%).¹H-NMR (CD₃OD; 400 MHz): δ 8.44 (d, 1H, J=9.6 Hz), 6.95 (d, 1H, J=9.6Hz), 4.13 (app t, 4H, J=5.2 Hz), 3.87-3.79 (m, 2H), 3.71-3.60 (m, 2H),3.42 (app t, 4H, J=5.2 Hz), 2.09-2.00 (m, 2H), 1.99-1.88 (m, 1H),1.69-1.55 (m, 2H), 1.09 (d, 3H, J=6.8 Hz). LC-MS (ESI, m/z): Calcd. forC₁₅H₂₃N₅O₂, 306.2 (M+H), found 306.1.

d) 2-Chloro-1-morpholin-4-yl-ethanone

A solution of morpholine (0.50 g, 5.7 mmol) in CH₂Cl₂ (10 mL) wastreated with Et₃N and cooled to 0° C. The mixture was treated withchloroacetyl chloride (0.50 mL, 6.3 mmol) as a solution in CH₂Cl₂ (2mL). The reaction was stirred at 0° C. for 15 min and then at roomtemperature for 30 min. The reaction was diluted with CH₂Cl₂ and washedwith water. The organic layer was dried over MgSO₄ and concentrated invacuo to afford the title compound (0.72 g, 76%) as a colorless oil.¹H-NMR (CDCl₃; 400 MHz): δ 4.06 (s, 2H), 3.73-7.67 (m, 4H), 3.62 (app t,2H, J=4.0 Hz), 3.52 (app t, 2H, J=4.0 Hz).

e)2-[4-(4-Methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-1-yl]-1-morpholin-4-yl-ethanone

A solution of4-methyl-3′-nitro-6′-piperazin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyldihydrobromide (as prepared in Example 67, step (c), 0.10 g, 0.21 mmol)in CH₂Cl₂ (5 mL) was treated with Et₃N (0.10 mL, 0.75 mmol) and2-chloro-1-morpholin-4-yl-ethanone (as prepared in the previous step, 39mg, 0.24 mmol). The reaction stirred at room temperature for 18.5 h. Thereaction was diluted with CH₂Cl₂ and washed with water. The aqueouslayer was further extracted with CH₂Cl₂. The combined organic layerswere dried over MgSO₄ and concentrated in vacuo to afford the titlecompound (0.11 g, 117%, some salt remains) as a yellow solid, which wasused directly in the next step without further purification. ¹H-NMR(CDCl₃; 400 MHz): δ 8.19 (d, 1H, J=9.2 Hz), 6.02 (d, 1H, J=9.2 Hz),3.76-3.67 (m, 8H), 3.26 (br s, 2H), 3.14-3.07 (m, 2H), 3.03-2.93 (m,2H), 2.63 (br s, 4H), 1.74-1.65 (m, 2H), 1.65-1.58 (m, 1H), 1.45-1.39(m, 3H), 1.37-1.24 (m, 3H), 0.97 (d, 3H, J=6.4 Hz). LC-MS (ESI, m/z):Calcd. for C₂₁H₃₂N₆O₄, 433.2 (M+H), found 433.1.

f)2-[4-(3′Amino-4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-1-morpholin-4-yl-ethanone

A solution of2-[4-(4-2-ethyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-1-yl]-1-morpholin-4-yl-ethanone(as prepared in the previous step, 0.11 g, 0.25 mmol) in 2:1 EtOH:water(15 mL) was treated with NH₄Cl (0.14 g, 2.5 mmol) and was heated to 100°C. Iron powder (70.4 mg, 1.26 mmol) was added and the reaction stirredat 100° C. for 2 h. The reaction was neutralized with saturated aqueousNaHCO₃ and extracted with CH₂Cl₂. The combined organic layers were driedover MgSO₄ and concentrated in vacuo to afford the title compound (0.10g, 98%), which was used immediately in the next reaction.

g) 5-Cyano-furan-2-carboxylic acid{4-methyl-6′-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl}-amide

A solution of 5-cyano-furan-2-carboxylic acid (as prepared in Example 1,70 mg, 0.51 mmol) in CH₂Cl₂ (5 mL) and DMF (30 μL) was treated withoxalyl chloride (49 μL, 0.56 mmol) and stirred at room temperature for 1h; The solvents were evaporated in vacuo. The residue was taken up inCH₂Cl₂ (5 mL). A solution of2-[4-(3′amino-4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-1-morpholin-4-yl-ethanone(as prepared in the previous step, 0.10 g, 0.25 mmol) was treated withDIEA (66 μL, 0.38 mmol) and cooled to 0° C. The solution of acidchloride generated above was added dropwise, and the reaction wasstirred at room temperature for 19 h. The reaction was diluted withCH₂Cl₂ and washed with water. The combined aqueous layers were extractedwith CH₂Cl₂. The combined organic layers were dried over MgSO₄ andconcentrated in vacuo. Silica gel chromatography (25-100% EtOAc inhexane, then 1-10% MeOH in CH₂Cl₂) afforded the title compound (14 mg,11%) as a white solid. ¹H-NMR (CDCl₃; 400 MHz): δ 8.76 (br s, 1H),8.43-8.39 (m, 1H), 7.24 (d, 1H, J=3.6 Hz), 7.21 (d, 1H, J=3.6 Hz), 6.36(d, 1H, J=8.8 Hz), 3.71-3.61 (m, 8H), 3.55-3.48 (m, 4H), 3.24 (s, 2H),3.22-3.15 (m, 2H), 2.88-2.79 (m, 2H), 2.66-2.60 (m, 4H), 1.84-1.76 (m,2H), 1.64-1.52 (m, 1H), 1.4-1.36 (m, 2H), 1.04 (d, 3H, J=6.4 Hz). LC-MS(ESI, m/z): Calcd. for C₂₇H₃₅N₇O₄, 522.3 (M+H), found 522.2.

Example 68 5-Cyano-furan-2-carboxylicacid{4-methyl-6′-[4-(2-morpholin-4-yl-acetyl)-piperazin-1-yl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl}-amidetrifluoroacetic acid salt

a)2-Chloro-1-[4-(4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-1-yl]-ethanone

A solution of4-methyl-3′-nitro-6′-piperazin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyldihydrobromide (as prepared in Example 67, step (c), 0.28 g, 0.60 mmol)in CH₂Cl₂ (6 mL) was treated with Et₃N (0.27 mL, 1.9 mmol) and cooled to0° C. The mixture was treated with chloroacetyl chloride (53 μL, 0.66mmol) as a solution in CH₂Cl₂ (2 mL) and stirred at 0° C. for 15 minthen at room temperature for 30 min. The reaction was diluted withCH₂Cl₂ and washed with water. The organic layer was dried over MgSO₄ andconcentrated in vacuo to afford the title compound (0.18 g, 80%) as ayellow solid. ¹H-NMR (CDCl₃; 400 MHz): δ 8.21 (d, 1H, J=9.2 Hz), 6.03(d, 1H, J=9.2 Hz), 4.11 (s, 2H), 3.84-3.76 (m, 4H), 3.76-3.61 (m, 4H),3.13-3.05 (m, 1H), 3.04-2.92 (m, 2H), 1.7-1.66 (m, 2H), 1.45-1.38 (m,2H), 1.38-1.25 (m, 2H), 0.98 (d, 3H, J=6.4 Hz). LC-MS (ESI, m/z): Calcd.for C₁₇H₂₄ClN₅O₃, 382.1 (M+H), found 382.1.

b)1-[4-(4-Methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-1-yl]-2-morpholin-4-yl-ethanone

A solution of2-chloro-1-[4-(4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-1-yl]-ethanone(as prepared in the previous step, 0.18 g, 0.48 mmol) in CH₂Cl₂ (10 mL)was treated with Et₃N (0.10 mL, 0.72 mmol) and morpholine (46 μL, 0.53mmol). The reaction was stirred at room temperature for 18.5 h. Thereaction was diluted with CH₂Cl₂ and washed with water. The aqueouslayer was extracted further with CH₂Cl₂. The combined organic layerswere dried over MgSO₄ and concentrated in vacuo to afford the titlecompound (0.16 g, 76%) as a yellow solid. ¹H-NMR (CDCl₃; 400 MHz): δ8.21 (d, 1H, J=9.2 Hz), 6.03 (d, 1H, J=9.2 Hz), 3.85-3.63 (m, 12H),3.32-3.22 (m, 2H), 3.05-2.93 (m, 2H), 2.66-2.50 (m, 2H), 1.75-1.66 (m,2H), 1.66-1.60 (m, 2H, partially obscured by water peak), 1.44-1.38 (m,1H), 1.37-1.16 (m, 4H), 0.98 (d, 3H, J=6.4 Hz). LC-MS (ESI, m/z): Calcd.for C₂₁H₃₂N₆O₄, 433.2 (M+H), found 432.9.

c)1-[4-(3′-Amino-4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-1-yl]-2-morpholin-4-yl-ethanone

A solution of1-[4-(4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-1-yl]-2-morpholin-4-yl-ethanone(as prepared in the previous step, 0.16 g, 0.37 mmol) in 2:1 EtOH:water(3 mL) was treated with NH₄Cl (0.20 g, 3.7 mmol) and iron powder (0.10g, 1.8 mmol). The reaction was heated to 100° C. for 50 min then cooledto room temperature. The mixture was neutralized with saturated aqueousNaHCO₃ and extracted with CH₂Cl₂. The combined organic layers were driedover MgSO₄ and concentrated in vacuo to afford the title compound (0.14g, 100%), which was immediately used in the next reaction.

d) 5-Cyano-furan-2-carboxylic acid{4-methyl-6′-[4-(2-morpholin-4-yl-acetyl)-piperazin-1-yl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl}-amidetrifluoroacetic acid salt

A solution of 5-cyano-furan-2-carboxylic acid (as prepared in Example 1,0.10 g, 0.79 mmol) in CH₂Cl₂ (5 mL) and DMF (30 μL) was treated withoxalyl chloride (70 μL, 0.81 mmol) and stirred at room temperature for 1h. The solvents were evaporated in vacuo, and the residue was taken upin CH₂Cl₂ (5 mL). A solution of1-[4-(3′-amino-4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-1-yl]-2-morpholin-4-yl-ethanone(as prepared in the previous step, 0.14 g, 0.37 mmol) was treated withDIEA (0.13 mL, 0.74 mmol) and cooled to 0° C. The solution of acidchloride generated above was added dropwise, and the reaction wasstirred at room temperature for 21 h. The reaction was diluted withCH₂Cl₂ and washed with water. The combined aqueous layers were extractedwith CH₂Cl₂. The combined organic layers were dried over MgSO₄ andconcentrated in vacuo. Reversed-phase HPLC (C-18 column) (10-50%acetonitrile in water with 0.1% TFA, over 30 min) afforded the titlecompound (22 mg, 11%) as a white solid. ¹H-NMR (CDCl₃; 400 MHz): δ 8.75(br s, 1H), 8.44 (d, 1H, J=8.8 Hz), 7.25 (d, 1H, J=4.0 Hz), 7.22 (d, 1H,J=4.0 Hz), 6.38 (d, 1H, J=8.8 Hz), 3.78-3.70 (m, 8H), 3.55 (app t, 2H,J=6.0 Hz), 3.47 (app t, 2H, J=6.0 Hz), 3.23 (s, 2H), 3.22-3.17 (m, 2H),2.89-2.80 (m, 2H), 2.57-2.50 (m, 4H), 1.86-1.78 (m, 2H), 1.59-1.54 (m,1H), 1.49-1.36 (m, 2H), 1.05 (d, 3H, J=6.4 Hz). LC-MS (ESI, m/z): Calcd.for C₂₇H₃₅N₇O₄, 522.3 (M+H), found 522.2.

Example 69 5-Cyano-furan-2-carboxylic acid[2-(4-fluoro-piperidin-1-yl)-4-(4-methyl-piperazin-1-yl)-phenyl]-amidetrifluoroacetic acid salt

a) 1-(5-Chloro-2-nitro-phenyl)-4-fluoro-piperidine

A solution of 4-chloro-2-fluoro-1-nitro benzene (0.30 g, 1.7 mmol) intoluene (5 mL) was treated with solid Na₂CO₃ (0.40 g, 3.7 mmol) and4-fluoropiperidine hydrochloride (0.25 g, 1.8 mmol). The reaction washeated to 40° C. for 6 h. The reaction was diluted with EtOAc and washedwith water. The organic layer was dried over MgSO₄ and concentrated invacuo to afford the title compound (0.44 g, 99%) as a bright yellow oil.¹H-NMR (CDCl₃; 400 MHz): δ 7.79 (d, 1H, J=8.8 Hz), 7.10 (d, 1H, 2.0 Hz),6.97 (dd, 1H, J=8.8 Hz, J=2.0 Hz), 4.97-4.79 (m, 1H), 3.26-3.17 (m, 2H),3.06-2.99 (m, 2H), 2.14-1.97 (m, 4H). LC-MS (ESI, m/z): Calcd. forC₁₁H₁₂ClFN₂O₂, 225.2 (M-Cl+2H), found 225.2.

b) 1-[3-(4-Fluoro-piperidin-1-yl)-4-nitro-phenyl]-4-methyl-piperazine

A solution of 1-(5-chloro-2-nitro-phenyl)-4-fluoro-piperidine (asprepared in the previous step, 0.44 g, 1.7 mmol) in 4-methylpiperazine(2 mL) was heated to 80° C. for 18.5 h. The solution was cooled to roomtemperature, diluted with CH₂Cl₂, and washed with water. The aqueouslayer was further extracted with CH₂Cl₂. The combined organic layerswere dried over MgSO₄ and concentrated in vacuo to afford the titlecompound (0.51 g, 93%) as a bright yellow solid. ¹H-NMR (CDCl₃; 400MHz): δ 8.04 (d, 1H, J=9.2 Hz), 6.45 (dd, 1H, J=9.2 Hz, J=2.4 Hz), 6.34(d, 1H, J=2.4 Hz), 4.97-4.79 (m, 1H), 3.38 (app t, 4H, J=5.2 Hz),3.26-3.15 (m, 4H), 3.07-2.98 (m, 4H), 2.54 (app t, 4H, J=5.2 Hz), 2.35(s, 3H). LC-MS (ESI, m/z): Calcd. for C₁₆H₂₃FN₄O₂, 323.2 (M+H), found323.2.

c) 2-(4-Fluoro-piperidin-1-yl)-4-(4-methyl-piperazin-1-yl)-phenylamine

A solution of1-[3-(4-fluoro-piperidin-1-yl)-4-nitro-phenyl]-4-methyl-piperazine (asprepared in the previous step, 0.20 g, 0.62 mmol) in 2:1 EtOH:water (6mL) was treated with solid NH₄Cl (0.33 g, 6.2 mmol) and iron powder(0.17 g, 3.1 mmol) then heated to 100° C. for 2.5 h. The reaction wascooled to room temperature, treated with 1 drop of glacial acetic acid,and heated again to 100° C. for 30 min. The reaction was cooled to roomtemperature and neutralized with saturated aqueous NaHCO₃. The productwas extracted with CH₂Cl₂, and the combined organic layers were driedover MgSO₄ and concentrated in vacuo to afford the title compound (0.19g, 99%), which was used immediately in the next reaction. LC-MS (ESI,m/z): Calcd. for C₁₆H₂₅FN₄, 293.2 (M+H), found 293.1.

d) 5-Cyano-furan-2-carboxylic acid[2-(4-fluoro-piperidin-1-yl)-4-(4-methyl-piperazin-1-yl)-phenyl]-aidetrifluoroacetic acid salt

Using a procedure similar to Example 68, step (d),2-(4-fluoro-piperidin-1-yl)-4-(4-methyl-piperazin-1-yl)-phenylamine (asprepared in the previous step, 0.19 g, 0.62 mmol) was coupled to5-cyano-furan-2-carboxylic acid (as prepared in Example 1, 85 mg, 0.62mmol). Reversed-phase HPLC (C-18 column) (10-50% acetonitrile in waterwith 0.1% TFA over 30 min) afforded the title compound (7.5 mg, 3%) as awhite solid. ¹H-NMR (CDCl₃; 400 MHz): δ 9.44 (br s, 1H), 8.32 (d, 1H,J=8.8 Hz), 7.30-7.26 (m, 1H), 7.25-7.21 (m, 1H), 6.82 (d, 1H, J=2.8 Hz),6.75 (dd, 1H, J=8.8 Hz, J=2.8 Hz), 5.06-4.85 (m, 1H), 3.34-3.26 (m, 4H),3.15-3.06 (m, 2H), 2.95-2.86 (m, 4H), 2.86-2.77 (m, 2H), 251 (s, 3H),2.17-2.10 (m, 4H). LC-MS (ESI, m/z): Calcd. for C₂₂H₂₆FN₅O₂ 412.2 (M+H),found 412.2.

Example 70 4-Cyano-1H-imidazole-2-carboxylic acid[2-(3-fluoro-piperidin-1-yl)-4-(4-methyl-piperazin-1-yl)-phenyl]-aminetris(trifluoroacetic acid salt)

a) 1-(5-Chloro-2-nitro-phenyl)-3-fluoro-piperidine

A solution of 4-chloro-2-fluoro-1-nitro-benzene (0.30 g, 1.7 mmol) intoluene (5 mL) was treated with solid Na₂CO₃ (0.40 g, 3.7 mmol) and3-fluoropiperidine (0.25 mg, 1.8 mmol) and heated to 40° C. for 6 h. Thereaction was diluted with EtOAc and washed with water. The organic layerwas dried over MgSO₄ and concentrated in vacuo to afford the titlecompound (0.43 g, 98%) as a bright yellow oil. ¹H-NMR (CDCl₃; 400 MHz):δ 7.76 (d, 1H, J=8.8 Hz), 7.11 (d, 1H, J=2.4 Hz), 6.95 (dd, 1H, J=8.8,2.4 Hz), 4.86-4.67 (m, 1H), 3.46-3.35 (m, 1H), 3.15-3.06 (m, 2H),2.99-2.92 (m, 1H), 2.10-1.90 (m, 2H), 1.88-1.69 (m, 2H). LC-MS (ESI,m/z): Calcd. for C₁₁H₁₂ClFN₂O₂ 259.1 (M+H), found 259.1.

b) 1-[3-(3-Fluoro-piperidin-1-yl)-4-nitro-phenyl]-4-methyl-piperazine

A solution of 1-(5-chloro-2-nitro-phenyl)-3-fluoro-piperidine (asprepared in the previous step, 0.44 g, 1.7 mmol) in N-methylpiperazine(2 mL) was heated to 80° C. for 18.5 h. The reaction was cooled to roomtemperature, diluted with CH₂Cl₂ and washed with water. The aqueouslayer was extracted with CH₂Cl₂. The combined organic layers were driedover MgSO₄ and concentrated in vacuo to afford the title compound (0.50g, 93%) as a yellow solid. ¹H-NMR (CDCl₃; 400 MHz): δ 8.00 (d, 1H, J=9.2Hz), 6.44 (dd, 1H, J=9.2 Hz, J=2.8 Hz), 6.34 (d, 1H, J=2.8 Hz),4.91-4.71 (m, 1H), 3.54-3.44 (m, 1H), 3.41-3.36 (m, 4H), 3.18-3.10 (m,1H), 3.02-2.94 (m, 1H), 2.87-2.80 (m, 1H), 2.5-2.52 (m, 4H), 2.35 (s,3H), 1.82-1.66 (m, 4H). LC-MS (ESI, m/z): Calcd. for C₁₆H₂₃FN₄O₂ 323.2(M+H), found 323.2.

c) 2-(3-Fluoro-piperidin-1-yl)-4-(4-methyl-piperazin-1-yl)-phenylamine

A solution of1-[3-(3-fluoro-piperidin-1-yl)-4-nitro-phenyl]4-methyl-piperazine (asprepared in the previous step, 60 mg, 0.19 mmol) in 2:1 EtOH:water (6mL), was treated with glacial AcOH (1 drop) and iron powder (10 mg, 0.93mmol). The mixture was heated to 80° C. for 30 min. The reaction cooledto room temperature, diluted with EtOAc and washed with saturatedaqueous NaHCO₃. The aqueous layer was extracted with EtOAc. The combinedorganic layers were dried over MgSO₄ and concentrated in vacuo to affordthe title compound (46 mg, 84%), which was used directly in the nextreaction. LC-MS (ESI, m/z): Calcd. for C₁₆H₂₅FN₄ 293.2 (M+H), found293.2.

d) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-(3-fluoro-piperidin-1-yl)-4-(4-methyl-piperazin-1-yl)-phenyl]-amide

A suspension of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (as prepared in Example 3, step (d), 48 mg, 0.16 mmol) inCH₂Cl₂ (5 mL) was treated with DIEA (68 μL, 0.39 mmol) and PyBroP (0.11g, 0.24 mmol). The reaction stirred at room temperature for 10 min. Asolution of2-(3-fluoro-piperidin-1-yl)-4-(4-methyl-piperazin-1-yl)-phenylamine (asprepared in the previous step, 46 mg, 0.16 mmol) in CH₂Cl₂ (4 mL) wasadded, and the reaction was stirred at room temperature for 19.5 h. Thereaction was diluted with CH₂Cl₂ and washed with saturated aqueousNaHCO₃ and water. The organic layer was dried over MgSO₄ andconcentrated in vacuo to afford the title compound (62 mg, 70%) as anoff-white solid, which was used directly in the next reaction. LC-MS(ESI, m/z): Calcd. for C₂₇H₄₀FN₇O₂Si, 542.3 (M+H), found 542.4.

e) 4-Cyano-1H-imidazole-2-carboxylic acid[2-(3-fluoro-piperidin-1-yl)-4-(4-methyl-piperazin-1-yl)-phenyl]-amidetris(trifluoroacetic acid salt)

A solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-(3-fluoro-piperidin-1-yl)-4-(4-methyl-piperazin-1-yl)-phenyl]-amide(as prepared in the previous step, 85 mg, 0.16 mmol) in CH₂Cl₂ (20 mL)was treated with TFA (2 mL) and stirred at room temperature for 15 h.The solvent was evaporated in vacuo. Silica gel chromatography (10% MeOHin EtOAc with 0.1% DIEA) followed by reversed-phase HPLC (C-18 column)(10-50% acetonitrile in water with 0.1% TFA over 30 min) afforded thetitle compound (21 mg, 26%) as a white solid. ¹H-NMR (CDCl₃; 400 MHz): δ8.27-8.22 (m, 1H), 7.72 (s, 1H), 6.78-6.72 (m, 2H), 4.98-4.78 (m, 1H),3.67 (m, 7H), 3.26-3.16 (m, 2H), 2.95-2.85 (m, 5H), 2.78-2.69 (m, 1H),2.22-2.00 (m, 2H), 1.93-1.69 (m, 2H). LC-MS (ESI, n/z): Calcd. forC₂₁H₂₆FN₇O 412.2 (M+H), found 412.1.

Example 71

An alternate method for the synthesis of the intermediate described inExample 1 is described below.

5-Cyano-furan-2-carboxylic acid

A 250-mL, three-neck, round-bottom flask equipped with a mechanicalstirrer, a heating mantle, and a condenser was charged with5-formyl-2-furancarboxylic acid (9.18 g, 65.6 mmol) and pyridine (60mL). Hydroxylamine hydrochloride (5.01 g, 72.2 mmol) was added and themixture was heated to 85° C. Acetic anhydride (40 mL) was added and thereaction was stirred at 85° C. for 3 h, after which time the solvent wasevaporated at 40° C. under reduced pressure. The residue was dissolvedin water, basified with 2.0 N NaOH solution to pH 9, and extracted with4:1 dichloromethane/2-propanol until the pyridine was completely removed(5×200 mL). The aqueous solution was then acidified with 2.0 N HClsolution to pH 2, saturated with solid NaCl, and extracted with 4:1dichloromethane/2-propanol (5×200 mL). The combined organic extractswere dried over Na₂SO₄ and concentrated in vacuo to dryness. The residuewas crystallized from dichloromethane to give 6.80 g of the titlecompound as a white solid (76%). Mass spectrum (ESI-neg, m/z) Calcd. forC₆H₃NO₃, 136.0 (M−H), found 136.1. The ¹H NMR spectrum was consistentwith the assigned structure.

Example 72

An alternate method for the synthesis of the imidazole intermediate isdescribed below:

4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid potassium salt

a) 1H-Imidazole-4-carbonitrile

A 22-L, four-neck, round-bottom flask equipped with a mechanicalstirrer, a temperature probe, a condenser, and an addition funnel with anitrogen inlet was charged with 1H-imidazole-4-carboxaldehyde (Aldrich,1.10 kg, 11.5 mol) and pyridine (3.0 L, 3.0 mol). The reaction flask wascooled to 8° C. with an ice bath and hydroxylamine hydrochloride (871 g,12.5 mol) was added slowly in portions to maintain the internaltemperature below 30° C. The reaction was allowed to cool to ambienttemperature and stirred for 2 h at ambient temperature. The resultingthick yellow solution was heated to 80° C. with a heating mantle andacetic anhydride (2.04 L, 21.6 mol) was added dropwise over 200 min tomaintain the temperature below 110° C. during the addition. The reactionmixture was heated at 100° C. for 30 min, after which time it wasallowed to cool to ambient temperature and then further cooled in an icebath. The pH was adjusted to 8.0 (pH meter) by the addition of 25 wt %NaOH (5.5 L) at such a rate that the internal temperature was maintainedbelow 30° C. The reaction mixture was then transferred into a 22-Lseparatory funnel and extracted with ethyl acetate (6.0 L). The combinedorganic layer was washed with brine (2×4.0 L), dried over MgSO₄,filtered, and concentrated to dryness under reduced pressure at 35° C.to give the crude product as a yellow semisolid. The resulting semisolidwas suspended in toluene (3.0 L) and stirred for 1 h, after which timeit was filtered to give a light yellow solid, which was resuspended intoluene (3.0 L) and stirred for 1 h. The resulting slurry was filteredand the filter cake washed with toluene (2×500 mL) to give the titlecompound as a light yellow solid [870 g, 82%). The ¹H and ¹³C NMRspectra were consistent with the assigned structure.

b) 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile and3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carbonitrile

A 22-L, four-neck, round-bottom flask equipped with a mechanicalstirrer, a temperature probe, and an addition funnel with a nitrogeninlet was charged with 1H-imidazole-4-carbonitrile (830 g, 8.91 mol, asprepared in the previous step), potassium carbonate (2.47 kg, 17.8 mol),and acetone (6.0 L). Agitation was initiated and the mixture was cooledto 10° C. with an ice bath. SEMCl (1.50 kg, 9.00 mol) was added throughthe addition funnel over 210 min to maintain the internal temperaturebelow 15° C. The reaction was then allowed to warm to ambienttemperature and stirred at ambient temperature overnight (20 h). Thereaction mixture was then cooled in an ice bath to 10° C. and quenchedby the slow addition of water (8.0 L) over 30 min to maintain theinternal temperature below 30° C. The resulting mixture was transferredto a 22-L separatory funnel and extracted with ethyl acetate (2×7.0 L).The combined organics were concentrated under reduced pressure at 35° C.to give the crude product as a dark brown oil, which was purifiedthrough a plug of silica gel (16.5×20 cm, 2.4 kg silica gel) using 2:1heptane/ethyl acetate (15 L) as eluent. The fractions containing theproduct were combined and concentrated under reduced pressure at 35° C.to afford a mixture of the title compounds as a light brown oil [1785 g,90%). The ¹H NMR spectrum was consistent with the assigned structure andindicated the presence of a 64:36 ratio of regioisomers.

c)2-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile

A 22-L, four-neck, round-bottom flask equipped with a mechanicalstirrer, a temperature probe, and a condenser with a nitrogen inlet wascharged with a mixture of1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile and3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carbonitrile [600 g,2.69 mol, as prepared in the previous step) and carbon tetrachloride(1.8 L). Agitation was initiated and the mixture was heated to 60° C. Atthis point N-bromosuccinimide (502 g, 2.82 mol) was added in severalportions over 30 min, which resulted in an exotherm to 74° C. Thereaction was allowed to cool to 60° C. and further stirred at 60° C. for1 h. The reaction was allowed to cool slowly to ambient temperature andthe resulting slurry was filtered and the filtrate washed with satdNaHCO₃ solution (4.0 L). The organics were passed through a plug ofsilica gel (8×15 cm, silica gel; 600 g) using 2:1 heptane/ethyl acetate(6.0 L) as eluent. The fractions containing the product (based on TLCanalysis) were combined and concentrated under reduced pressure to givea crystalline light yellow solid, which was then filtered and washedwith heptane (500 mL) to give the title compound as a crystalline whitesolid [593 g, 73%). The ¹H and ¹³C NMR spectra were consistent with theassigned structure and showed no evidence of the minor regioisomers.

d) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester

A 12-L, four-neck, round-bottom flask equipped with a mechanicalstirrer, a temperature probe, and an addition funnel with a nitrogeninlet was charged with2-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile[390 g, 1.29 mol, as prepared in the previous step) and anhydroustetrahydrofuran (4.0 L). Agitation was initiated and the reactionmixture was cooled to −50° C. using a dry ice/acetone bath.Isopropylmagnesium chloride (2.0 M in THF, 760 mL, 1.52 mol) was addedthrough the addition funnel over 30 min to maintain the internaltemperature below −40° C. The reaction was stirred for a further 30 minat −43° C., after which time it was cooled to −78° C. Ethylchloroformate (210 mL, 2.20 mol) was added through the addition funnelover 10 min to maintain the internal temperature below −60° C. Thereaction was stirred for a further 40 min at −70° C., at which point thedry ice/acetone bath was removed and the reaction was allowed to warm toambient temperature over 1.5 h. The reaction mixture was cooled in anice bath to 0° C. and quenched by the slow addition of satd ammoniumchloride solution (1.8 L) at such a rate that the internal temperaturewas maintained below 10° C. The reaction mixture was transferred into a12-L separatory funnel, diluted with ethyl acetate (4.0 L), and thelayers were separated. The organic layer was washed with brine (2×2.0 L)and concentrated under reduced pressure at 35° C. to give a brown oil.The crude oil was dissolved in dichloromethane (300 mL) and purified bychromatography (15×22 cm, 1.5 kg of silica gel, 10:1 to 4:1heptane/ethyl acetate) to give a yellow oil, which was dissolved inEtOAc (100 mL), diluted with heptane (2.0 L), and stored in arefrigerator for 5 h. The resulting slurry was filtered to give thetitle compound as a crystalline white solid (141 g, 37%). The ¹H and ¹³CNMR spectra were consistent with the assigned structure.

e) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid potassium salt

A 5-L, three-neck, round-bottom flask equipped with a mechanicalstirrer, a temperature probe, and an addition funnel with a nitrogeninlet was charged with 5 [400 g, 1.35 mol) and ethanol (4.0 L).Agitation was initiated and a water bath was applied after all of thesolid had dissolved. A solution of 6 N KOH (214.0 mL, 1.29 mol) wasadded through the addition funnel over 15 min to maintain the internaltemperature below 25° C. and the reaction was stirred for 5 min at roomtemperature. The solution was then concentrated to dryness under reducedpressure at 20° C. to give a white solid. The resulting solid wassuspended in methyl t-butyl ether (MTBE, 4.0 L) and stirred for 30 min,after which time the slurry was filtered and the filter cake washed withMTBE (1.0 L) to give the title compound as a white solid, which wasfurther dried under vacuum at ambient temperature for 4 d [366 g, 89%).The ¹H NMR, ¹³C NMR, and mass spectra were consistent with the assignedstructure. Anal. Calcd for C₁₁H₁₆KN₃O₃Si: C, 43.25; H, 5.28; N, 13.76.Found: C, 42.77; H, 5.15; N, 13.37. Karl Fisher: 1.3% H₂O.

IV. Results

An autophosphorylation, fluorescence polarization competitionimmunoassay was used to determine the potency for c-fms inhibitionexhibited by selected compounds of Formula I. The assay was performed inblack 96-well microplates (LJL BioSystems). The assay buffer used was100 mM 4-(2-hydroxyethyl)piperazine 1-ethanesulfonic acid (HEPES), pH7.5, 1 mM 1,4-dithio-DL-threitol (DTT), 0.01% (v/v) Tween-20. Compoundswere diluted in assay buffer containing 4% dimethylsulfoxide (DMSO) justprior to the assay. To each well, 5 μL of compound were added followedby the addition of 3 μL of a mix containing 33 nM c-fms (Johnson &Johnson PRD) and 16.7 mM MgCl₂ (Sigma) in assay buffer. The kinasereaction was initiated by adding 2 μL of 5 mM ATP (Sigma) in assaybuffer. The final concentrations in the assay were 10 nM c-fms, 1 mMATP, 5 mM MgCl₂, 2% DMSO. Control reactions were ran in each plate: inpositive and negative control wells, assay buffer (made 4% in DMSO) wassubstituted for the compound; in addition, positive control wellsreceived 1.2 μL of 50 mM ethylenediaminetetraacetic acid (EDTA).

The plates were incubated at room temperature for 45 min. At the end ofthe incubation, the reaction was quenched with 1.2 μL of 50 mM EDTA(EDTA was not added to the positive control wells at this point; seeabove). Following a 5-min incubation, each well received 10 μL of a1:1:3 mixture of anti-phosphotyrosine antibody, 10×, PTK green tracer,10× (vortexed), FP dilution buffer, respectively (all from PanVera, cat.#P2837). The plate was covered, incubated for 30 min at room temperatureand the fluorescence polarization was read on the Analyst. Theinstrument settings were: 485 nm excitation filter; 530 nm emissionfilter; Z height: middle of well; G factor: 0.93. Under theseconditions, the fluorescence polarization values for positive andnegative controls were approximately 300 and 150, respectively, and wereused to define the 100% and 0% inhibition of the c-fms reaction. IC₅₀values are obtained as averages of three independent measurements.Compounds were classed as A, B, or C, with A: <0.020 μM; B: >0.020 μMand <0.050 μM; and C: >0.050 μM and <0.5 μM.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

All publications disclosed in the above specification are herebyincorporated by reference in full.

1. The compounds of Formula I:

or a tautomer or pharmaceutically acceptable salt thereof, wherein: A isphenyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, which may besubstituted with one of chloro, fluoro, methyl, —N₃, —NH₂, —NH(alkyl),—N(allyl)₂, —S(alkyl), —O(alkyl), alkylOC(O)alkyl, or 4-aminophenyl; Wis pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,2,4-triazolyl orfuranyl, any of which may be connected through any carbon atom, whereinthe pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,2,4-triazolyl, orfuranyl may contain one —CN, —NO₂, —OMe, C(═NH)NOH, or —CF₃substitution, connected to any other carbon; R² is piperidinyl, pyrrolylor pyrrolidinyl, any of which may be independently substituted, with oneor two of each of the following: chloro, fluoro, oxo, and C₍₁₋₃₎alkyl,with the proviso that R² is connected to the ring A through the nitrogenatom; X is

Z is CH or N; D¹ and D² are hydrogens or taken together form a doublebond to an oxygen; D³ and D⁴ are hydrogens or taken together form adouble bond to an oxygen; D⁵ is hydrogen or —CH₃, wherein said —CH₃ maybe relatively oriented syn or anti; R_(a) and R_(b) are independentlyhydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl; E is N, S, O, SO or SO₂, with the proviso that E may notbe N if the following three conditions are simultaneously met: Q_(a) isabsent, Q_(b) is absent, and R³ is an amino group or cyclic aminoradical wherein the point of attachment to E is N; Q_(a) is absent,—CH₂—, —CH₂CH₂—, or C(O); Q_(b) is absent, —NH—, —CH₂—, —CH₂CH₂—, orC(O), with the proviso that Q_(b) may not be C(O) if Q_(a) is C(O), andfurther provided that Q_(b) may not be —NH— if E is N and Q_(a) isabsent, further provided that Q_(b) may not be —NH— if R³ is an aminogroup or cyclic amino radical wherein the point of attachment to Q_(b)is N; R³ is hydrogen, phenyl, hydroxyalkylamino, (hydroxyalkyl)₂amino,hydroxyalkyl(alkyl)amino, alkylamino, aminoalkyl, dihydroxyalkyl,alkoxy, dialkylamino, hydroxyalkyl, —COOH, —CONH₂, —CN, —SO₂-alkyl-R⁴,—NH₂, or a 5- or 6-membered ring which contains at least one heteroatomN and may optionally contain an additional heteromoiety selected from S,SO₂, N, and O, and the 5- or 6-membered ring may be saturated, partiallyunsaturated or aromatic wherein aromatic nitrogen in the 5- or6-membered ring may be present as N-oxide, and the 5- or 6-membered ringmay be optionally substituted with methyl, halogen, alkylamino, oralkoxy; R³ may also be absent, with the proviso that R³ is not absentwhen E is nitrogen; R⁴ is hydrogen, —OH, alkoxy, carboxy, carboxamido,or carbamoyl.
 2. A compound of claim 1 wherein W is substituted with one—CN.
 3. A compound of claim 1 wherein A is pyridinyl, which may besubstituted with one of chloro, fluoro, methyl, —N₃, —NH₂, —NH(alkyl),—N(alkyl)₂, —S(alkyl), —O(alkyl), or 4-aminophenyl; W is imidazolyl,which may contain one —CN; and R² is piperidinyl.
 4. A compound of claim1 wherein: W is imidazolyl, 1,2,4-triazolyl or furanyl any of which maybe connected through any carbon atom, wherein the imidazolyl,1,2,4-triazolyl, or furanyl may contain one —CN, connected to any othercarbon; R² is piperidinyl, pyrrolyl or pyrrolidinyl; X is

E is N or SO₂, with the proviso that E may not be N if the followingthree conditions are simultaneously met: Q_(a) is absent, Q_(b) isabsent, and R³ is an amino group or cyclic amino radical wherein thepoint of attachment to E is N; and R³ is hydrogen, phenyl,hydroxyalkylamino, hydroxyalkyl(alkyl)amino, alkylamino, aminoalkyl,dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl, —COOH, —CONH₂, —CN,—SO₂CH₃, —NH₂, or a 5- or 6-membered ring selected from the groupconsisting of: piperidinyl, morpholinyl, imidazolyl, and pyrindinyl,wherein the 5- or 6-membered ring may be optionally substituted withmethyl, halogen, alkylamino, or alkoxy, R³ may also be absent, with theproviso that R³ is not absent when E is nitrogen.
 5. A compound of claim1 wherein: A is phenyl which may be substituted with one of chloro,fluoro, or methyl; X is

and is attached to the phenyl A ring para to the nitrogen substituent,as depicted in formula II;

D³ and D⁴ are hydrogen; E is N or SO₂, with the proviso that E may notbe N if the following three conditions are simultaneously met: Q_(a) isabsent, Q_(b) is absent, and R³ is an amino group or cyclic aminoradical wherein the point of attachment to E is N; and R³ is hydrogen,piperidinyl, alkylamino, dialkylamino, hydroxyalkylamino,(hydroxyalkyl)₂amino, imidazolyl, 1-methyl imidazolyl, pyridyl, pyridylN-oxide, hydroxyalkyl, —COOH, —CONH₂, —CN, —SO₂CH₃—, —NH₂, morpholinyl;R³ may also be absent, with the proviso that R³ is not absent when E isnitrogen.
 6. A compound of claim 5 wherein: A is phenyl; W isfuran-2-yl, 1H-pyrrol-2-yl, or 1H-imidazol-2-yl, any of which may besubstituted at the 4 or 5 carbons with —CN; R² is piperidinyl optionallysubstituted with chloro, fluoro, or C₍₁₋₃₎alkyl.
 7. A compound of claim6 wherein: W is 3H-2-imidazolyl-4-carbonitrile or5-cyano-1H-pyrrol-2-yl; R² is piperidinyl optionally substituted withfluoro or methyl; E is N, with the proviso that E may not be N if thefollowing three conditions are simultaneously met: Q_(a) is absent,Q_(b) is absent, and R³ is an amino group or cyclic amino radicalwherein the point of attachment to E is N; and Z is CH.
 8. A compound ofclaim 7 wherein: W is 3H-2-imidazolyl-4-carbonitrile; Q_(a) is C(O); R³is hydrogen, piperidinyl, alkylamino, dialkylamino, hydroxyalkylamino,(hydroxyalkyl)₂amino, imidazolyl, 1-methyl imidazolyl, pyridyl, pyridylN-oxide, hydroxyalkyl, —COOH, —CONH₂, —CN, —SO₂CH₃, —NH₂, morpholinyl;R³ may also be absent, with the proviso that R³ is not absent when isnitrogen.
 9. A compound selected from the group consisting of:5-Cyano-furan-2-carboxylic acid(4-morpholin-4-yl-2-piperidin-1-yl-phenyl)-amide;5-Cyano-furan-2-carboxylic acid(2-piperidin-1-yl-4-thiomorpholin-4-yl-phenyl)-amide;5-Cyano-furan-2-carboxylic acid[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-2-piperidin-1-yl-phenyl]-amide;5-Cyano-furan-2-carboxylic acid[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-2-piperidin-1-yl-phenyl]-amide;5-Cyano-furan-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-morpholin-4-yl-phenyl]-amide;4-Methyl-piperazine-1-carboxylic acid{4-[(5-cyano-furan-2-carbonyl)-amino]-3-piperidin-1-yl-phenyl}-methyl-amide;5-Cyano-furan-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amidehydrochloride; 5-Cyano-furan-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amidedihydrochloride; 5-Cyano-furan-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amidebis(trifluoracetic acid salt); 4-Cyano-1H-pyrrole-2-carboxylic acid[2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amidebis(trifluoracetic acid salt); 5-Cyano-furan-2-carboxylic acid[4-(1-acetyl-piperidin-4-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]l-amide;5-Cyano-1H-imidazole-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amidetrifluoroacetic acid salt; 3H-Imidazole-4-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amidebis(trifluoroacetic acid salt); 1H-Imidazole-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amidebis(trifluoroacetic acid salt); 3H-Imidazole-2,4-dicarboxylic acid2-amide4-{[4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide}trifluoroaceticacid salt; 1H-Imidazole-2-carboxylic acid[3-chloro-4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amidebis(trifluoroacetic acid salt); 4-Cyano-1H-pyrrole-2-carboxylic acid[4-[1-(imidazole-1-carbonyl)-piperidin-4-yl]-2-(4-methyl-piperidin-1-yl)-phenyl]-amide;4-Cyano-1H-pyrrole-2-carboxylic acid{2-(4-methyl-piperidin-1-yl)-4-[1-(pyridine-3-carbonyl)-piperidin-4-yl]-phenyl}-amide;4-Cyano-1H-pyrrole-2-carboxylic acid[4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-2-(4-methyl-piperidin-1-yl)-phenyl]-amide;4-Cyano-1H-pyrrole-2-carboxylic acid{2-(4-methyl-piperidin-1-yl)-4-[1-(2,2,2-trifluoroethyl)-piperidin-4-yl]-phenyl}-amide;4-Cyano-1H-imidazole-2-carboxylic acid[4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide;4-Cyano-1H-pyrrole-2-carboxylic acid{2-(4-methyl-piperidin-1-yl)-4-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-phenyl}-amide;4-Cyano-1H-pyrrole-2-carboxylic acid[4-[1-(2-methanesulfonyl-acetyl)-piperidin-4-yl]-2-(4-methyl-piperidin-1-yl)-phenyl]-amide;4-Cyano-1H-pyrrole-2-carboxylic acid[4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide;5-Cyano-furan-2-carboxylicacid[4-[4-methyl-piperazin-1-yl)-2-morpholin-4-yl-phenyl]-amide;5-Cyano-furan-2-carboxylicacid[2-(4-methyl-piperazin-1-yl)-4-(4-methyl-piperidin-1-yl)-pyrimidin-5-yl ]-amide trifluoroacetic acid salt; or pharmaceutically acceptablesalts thereof.
 10. A pharmaceutical composition, comprising a compoundof claim 1 and a pharmaceutically acceptable carrier.
 11. Apharmaceutical dosage form comprising a pharmaceutically acceptablecarrier and from about 0.5 mg to about 10 g of at least one compound ofclaim 1.